A Report: 6th International Conference on Nutrition and Growth Valencia, Spain March 7–9, 2019

As mentioned by the Organizing Committee, the purpose of the conference is to bring together pediatricians, nutritionists, neonatologists, experts in child development and other specialists to discuss the challenges of the interplay between Nutrition and Growth in the pediatric age group. It is also expected that the meeting will enable the exchange of ideas and knowledge between the different disciplines for facilitating research and clinical interdisciplinary collaborations focusing on nutrition and growth.

The conference started by a session “Before the First 1000 days: Before Conception and After Birth” presenting three topics, i.e. 1) influence of early nutritional factors on obesity in the offspring, 2) nutrition, conception and offspring epigenome, and 3) breastfeeding and growth. The following are the abstracts of each topic:

1. INFLUENCE OF EARLY NUTRITIONAL FACTORS ON OBESITY IN THE OFFSPRING

L. Moreno1. 1GENUD research group- Universidad de Zaragoza- Instituto Agroalimentario de Aragón IA2- Instituto de Investigación Sanitaria de Aragón IIS Aragón- Centro de Investigación Biomédica en red de Fisiopatología de la Obesidad y Nutrición CIBEROBN- Zaragoza- Spain, Facultad de Ciencias de la Salud, Zaragoza, Spain.

Childhood obesity is the most prevalent nutritional disorder during childhood. It develops in individuals with a genetic predisposition substrate and the presence of factors related with nutrition, sedentary behaviours and others as short sleep duration. During early periods of life, starting at conception and until the end of the second year, there is a large number of factors that could influence the development of obesity later in life: pre-pregnancy maternal body mass index (BMI), gestational weight gain, gestational diabetes, maternal malnutrition, maternal smoking during pregnancy, alcohol consumption during pregnancy, free sugars intake during pregnancy, low polyunsaturated fat (omega 3) intake during pregnancy, low physical activity levels during pregnancy, antibiotics consumption during pregnancy, high or low body weight at birth, lack of breast feeding, consumption of high protein content infant formulas, rapid infant weight gain, high protein, fat or free sugars intake during infancy, early introduction of complementary feeding and short sleep duration. From all these candidate risk factors, the ones more strongly associated with obesity development during childhood are maternal obesity before pregnancy, low birth weight and rapid weight gain during infancy. Perinatal factors also influence the expression of some genes related with obesity development. For instance, birth weight modifies the effect of the FTO gene polymorphism in the development of obesity and breastfeeding also modulate the effect of the PPAR-gamma 2 gene polymorphism on the excess of adiposity in adolescents. Interventions trying to prevent obesity should start as early as possible as the possibility to positively influence the early programming of the condition is optimal in this period.

1. nutrition, conception and offspring epigenome

M. Silver1. 1MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Nutrition, London, United Kingdom.

Our group has a long-standing interest in exploring links between early life nutritional exposures and long-term health outcomes. Much of our research centres on a rural community in The Gambia in Sub-Saharan West Africa.

A key focus is on epigenetics - the study of modifications to the genome that can affect gene expression without altering the underlying DNA sequence. Mounting evidence from animal and human studies suggests such modifications may mediate observed associations between early-life nutrition and later health and disease.

For our epigenetic studies we are able to exploit an ‘experiment of nature’ in rural Gambia whereby fluctuations in energy balance and maternal nutritional exposures show a distinct bimodal seasonal pattern. We have shown for example that season of conception and blood levels of key maternal nutritional biomarkers relating to one-carbon metabolism (B2, B6, cysteine and homocysteine) predict DNA methylation in infants at a number of metastable epialleles (MEs) - genomic regions where methylation is established stochastically in the early embryo, leading to systemic (cross-tissue) inter-individual variation.

I will give an overview of our work in this area and describe some of the interesting candidate MEs that we have selected for follow up in our population including a region at the POMC gene with links to obesity in children and adults.

1. breastfeeding and growth

K. Michaelsen1. 1Department of Nutrition- Exercise and Sports, University of Copenhagen, Denmark, Denmark.

Breastfeeding has a marked effect on early growth and there are some indications that there are also effects on growth later in life. Breastfed infants grow faster during the first 2-3 months and have thereafter a slower growth velocity up to the age of about 12 months, compared to infants that are not breastfed. This growth pattern, which is regarded as optimal, is also reflected in differences in body composition. There are studies suggesting a modest reduction in risk of obesity, but some studies show no effect. The vast majority of studies of the effect of breastfeeding on growth are observational and it is therefore difficult to conclude on causality as residual confounding and reverse causation are likely to influence the associations. There is an increasing number of studies examining the association between composition of breastmilk and growth of the infant. Especially the content of macronutrients, human milk oligosaccharides and appetite related hormones seem to have an effect on growth. A better understanding of these associations are likely to improve our understanding on how breastfeeding is regulating short and long term growth. Future studies should include analysis of milk composition and measurements of body composition when possible. Furthermore, data should also be analyzed according to sex as several studies have suggested that the association between milk intake and composition and growth is different in boys and girls.

During the session entitled Water, Sanitation and Hygiene (WASH) Intervention to Improve child Health, there are three topics presented, as follows:

1. Pathways linking wash and growth

S. Sinharoy1. 1Emory University, Environmental Health, Atlanta, USA.

The relationship between water, sanitation, and hygiene and child nutrition remains unclear, with mixed results from ecological and intervention studies. This presentation will provide an overview of key components of water, sanitation and hygiene (WaSH) and will outline the mechanisms and pathways through which WaSH may influence child nutritional status. Specifically, poor WaSH conditions may lead to diarrhea, environmental enteric dysfunction (a subclinical disorder of the small intestine), and intestinal parasitic infection. These in turn may result in undernutrition through appetite suppression, nutrient loss, malabsorption, and inflammation. Our understanding of these mechanisms provides a strong theoretical rationale for combining WaSH interventions to improve child nutrition. To illustrate how these relationships may operate in a real-world setting, the presentation will include results from a matched cohort effectiveness evaluation of a combined on-premise piped water and improved sanitation intervention in rural Odisha, India. We collected data in mid-2016 on anthropometry for children under age 5 (N=1826) in 45 intervention and 45 control villages. Children under age 5 living in communities that received the intervention had higher mean height-for-age z-score (HAZ) (+0.17 HAZ, 95% CI:0.03-0.31) compared to children in control villages. A structural modeling equation (SEM) approach quantified the direct and indirect intervention effects on HAZ through a complex system of divergent water, sanitation, and hygiene pathways. The results of the SEM analysis suggest that piped water and sanitation together influenced HAZ, and that both may be necessary for programs to impact child linear growth.

1. the shine and wash benefits trials

J. Humphrey1. 1Johns Hopkins Bloomberg School of Public Health, International Health- Center for Human Nutrition, Baltimore, USA.

The WASH Benefits Bangladesh, WASH Benefits Kenya, and Sanitation Infant Feeding Efficacy (SHINE, Zimbabwe) trials were cluster-randomized controlled trials to test the independent and combined effects of improving household water and sanitation/hygiene (WASH) and improving infant diet on child stunting and anemia at 18 mo (SHINE) or 24 mo (WASH Benefits trials). In addition, 7-day prevalence of diarrhea at 12 and 18 or 24 months was a primary outcome of WASH Benefits and secondary outcome of SHINE. Together the three trials included more than 18,000 children; provided free pit latrines, soap, chlorine, and lipid-based micronutrient supplement; delivered behaviour change modules based on years of formative research and pilot testing, and grounded in behaviour change theory, and measured outcomes by standardized and supervised research staff.

WASH Benefits included 7 arms [sanitation, handwashing with soap, point of use water chlorination, all these interventions combined (WASH), infant feeding, WASH+infant feeding, and a double sized control arm (passive in Bangladesh, active in Kenya)]. Thus, it was also designed to compare the benefits of single or combined WASH interventions. SHINE was a 2x2 factorial trials (WASH, Infant feeding, WASH+infant feeding, and an active control).

In all three trials:

• · the interventions were delivered with high fidelity and achieved substantial behavior change;

• · the infant feeding intervention had a modest benefit but WASH had no effect on stunting;

• · the infant feeding intervention improved haemoglobin but WASH had no effect on haemoglobin concentration.

In Bangladesh, all the intervention arms except water chlorination reduced diarrhea by a relative 30-40% from a very low prevalence (~5%); in the two Africa sites there was no effect of any intervention on diarrhea from a 10% prevalence in Zimbabwe and 27% prevalence in Kenya in the control arms.

This presentation will discuss:

• · The stunting results which contrast to a very large published literature of observational studies demonstrating that these same household level WASH interventions are strongly associated with stunting;

• · the differential results on diarrhea; and

• · the reasons why the trial interventions may have failed to reduce stunting.

1. where next? might wash interventions work?

A. Prentice1. 1MRC UNIT The Gambia at London School of Hygiene & Tropical Medicine, Nutrition, Keneba, United Kingdom.

Where Next? Might WASH++ interventions work? Andrew M Prentice, MRCG@LSHTM, Keneba, The Gambia Most children living in poor environments in low- and middle-income countries suffer from various forms of malnutrition of which stunting and anemia represent the most easily detectable syndromes. It has long been understood that the etiology of such conditions is not solely dependent on primary nutritional deficiencies, and that there are numerous so-called ‘nutrition sensitive’ causes that exacerbate the shortages of nutrients. Key amongst these is the issue of poor hygiene. The first presentation in this session, by Dr Sinharoy, will outline the mechanisms and pathways by which poor hygiene impairs nutrient uptake and utilisation. Combatting these effects ought to be possible by the implementation of interventions to improve water, sanitation and hygiene (WASH). The second presentation, by Dr Humphrey, will summarise the outcomes from the WASH Benefits and SHINE Trials in Bangladesh, Kenya and Zimbabwe. These were very large cluster-randomised trials to test the effectiveness of improving WASH and promoting better infant and young child feeding (IYCF). IYCF had a small benefit in each trial but there was no effect of WASH nor a positive interaction with IYCF. This final presentation will try to examine some of the possible reasons for these very disappointing results. Data from The Gambia suggest that there is a very high threshold of WASH that must be reached before growth will respond, and that it may be necessary to introduce piped water into homes to achieve the benefit. The challenges around such WASH++ or Transformative WASH solutions will be discussed.

The session on Growth, Nutrition and sport only provide one topic presented with its abstract entitled as follows:

eating patterns, food intake and supplements use in adolescent athletes

M. Yackobovitch-Gavan1. 1National Center for Childhood Diabetes- Schneider Children’s Medical Center of Israel., The Jesse Z and Lea Shafer Institute for Endocrinology and Diabetes, Petach Tikva, Israel.

Adolescence is a period of significant changes, including fast growth and physical development as well as social, emotional and sexual development, which has implications on how adolescents view themselves and on their sporting achievements. In terms of nutrition, adolescence is an important time in establishing an individual’s lifelong relationship with food.

Proper nutrition is especially vital for adolescents with a high activity level, as they experience numerous nutritional challenges, such as meeting nutrient needs for growth, maintenance of health, training and competing. Inadequate energy and nutrients consumption can cause growth retardation, delayed puberty, reduced accumulation of muscle and bone mass and increased susceptibility to fatigue, injury or illness.

According to the recent published data, Adolescent athletes usually do not adjust their nutrient intake to the demands of the training and do not meet nutritional recommendations. Many young athletes are using dietary supplements with the belief they will improve performance and health; however, may not always have reliable information. Special considerations in adolescent female athletes, mainly iron deficiency and disordered eating, should be addressed and studied.

To ensure that the adolescent athlete fulfils his or her potential (both, performance and physical growth), nutrition and eating patterns should be supported by a professional team. Further interventional RCTs are needed in this population.

While session on How to Achieve Optimal Growth in Preterm Infants provided two from three abstract presentation, as follows:

1. LONG TERM METABOLIC/ENDOCRINE OUTCOMES OF PREMATURITY AS CONSEQUENCE OF NUTRITIONAL MANAGEMENT

M. Finken1. 1Emma Children's Hospital- Amsterdam UMC, Pediatric Endocrinology, Amsterdam, The Netherlands.

Preterm birth is associated with long-term metabolic risks, such as abdominal fat distribution, insulin resistance, type 2 diabetes mellitus, and raised blood pressure. Early postnatal growth restriction is common among ill preterm infants, but should be avoided to enable the brain to develop optimally. In contrast, rapid weight gain in neonatal life and infancy could augment metabolic risks. The evidence from nutritional intervention studies aimed at the reduction of the long-term metabolic sequelae of preterm birth will be reviewed. More individualized nutritional care, based on the assumption that the long-term metabolic risks can be mitigated by ensuring appropriate linear growth without excess fat mass accretion, seems warranted.

1. LONG TERM COGNITIVE OUTCOMES OF PREMATURITY AS CONSEQUENCE OF NUTRITIONAL MANAGEMENT

M. de Pipaon1. 1MD, Neonatology, Madrid, Spain.

There is increasing evidence from preclinical and human studies that nutrition in the late foetal and early neonatal period has a significant impact on neurodevelopment across the lifespan. Large difference in intelligence between extremely or very preterm children and controls, which was stable in children born between 1990 and 2008. A fall in the weight z-score from birth to 36 weeks in very preterm infants could predict neurodevelopment. There is a positive association between nutrition during the first four weeks after birth and brain volumes. Moreover, a positive relationship between nutrition, white matter maturation at term equivalent age, and neurodevelopment in infancy. These findings emphasize the importance of a balanced protein, fat, and caloric content for brain development. Beneficial effects of breast milk on cognitive skills and behavior ratings have been demonstrated in term and very low birth weight infants. For every 10-mL/kg per day increase in breast milk ingestion, the Mental Development Index increased by 0.53 points, the Psychomotor Development Index increased by 0.63 points and the Behavior Rating Scale percentile score increased by 0.82 points. Brain imaging studies reveal increased white matter and sub-cortical gray matter volume, and parietal lobe cortical thickness, associated with IQ, in adolescents who were breastfed as infants compared to those who were exclusively formula-fed. Very preterm infants who received formula with an ω-6/ω-3 ratio of 2/1 had better psychomotor development, compared with very preterm newborns who consumed formula with an ω-6/ω-3 of 1/1. Therefore, formula milk with an arachidonic acid quantity double that of docosahexaenoic acid should be considered for feeding very preterm infants.

Plenary session on Yearbook provided three from eight presented topics with abstracts, as follows:

1. THE PHYSIOLOGY AND MECHANISM OF GROWTH

S. Demol1, P. Kotnik2, M. Phillip3, A. Faisal4. 1Schneider Children’s Medical Center of Israel, Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes- National Center for Childhood Diabetes-, Petach Tikva, Israel. 2Department of Endocrinology- Diabetes and Metabolism, University Children’s Hospital- University Medical Centre Ljubljana, Ljubljana, Slovenia. 3Schneider Children's Medical Center of Israel, The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes- National Center for Childhood Diabetes, Petach-Tikva, Israel. 4Royal Hospital for Sick Children- University of Glasgow, Developmental Endocrinology Research Group, Glasgow, United Kingdom.

The physiology of growth in children is still not fully elucidated. In recent years, with the availability of new technologies, our understanding of the interactions between the genetic, epigenetic, internal (microbiome) and external environments and children’s growth has increased.

The manuscripts published in peer-review journals in the past year (from July 1, 2017 to June 30, 2018) contributed to the expansion of our understanding of the physiology of growth and especially the interaction between nutrition and growth. The chapter covers various aspects in this field, including the effect of nutrition on growth, catch up growth in preterm and term infant, mechanisms of growth in the growth plate, the influence of nutrition and supplements on growth and puberty, and new tools to diagnose endo-genetic growth disorders.

1. MALNUTRITION AND CATCH-UP GROWTH DURING CHILDHOOD AND PUBERTY

N. Fisch1. 1Schneider Children’s Medical Center of Israel-, Jesse Z. and Sara Lea Shafer Institute of Endocrinology and Diabetes- National Center for Childhood Diabetes-, Petach Tikva, Israel.

Michal Yackobovitch-Gavan1,2, Naama Fisch Shvalb1,2 & Zulfiqar Bhutta3,4

1 Jesse Z. and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva ; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON, Canada; 4Center of Excellence in Women and Child Health, The Aga Khan University, Karachi, Pakistan.

This chapter of the 2019 yearbook reviews the most recent data on childhood malnutrition and catch-up growth, published between July 1, 2017 and June 30, 2018.

Two publications were selected for oral presentation. The first, by Krasevec et al., is a large cross-sectional study which evaluated the association between two indictors of dietary quality - dietary diversity and animal source food (ASF) consumption - and stunting. The analyses were based on data of 74,548 children aged 6–23 months, from demographic and health surveys in 39 different countries. The authors found a significant association both between dietary diversity and less stunting, and between the consumption of ASF and less stunting in infants aged 6-23 months. The number of food groups consumed and number of ASF on the previous day were associated with less stunting, in a dose response manner, even after adjusting for child, maternal, and household covariates.

The second publication by Christian et al. is a review on undernutrition in an under-studied population – adolescents. Normal adolescent growth, a process subject to endocrine control, is particularly sensitive to undernutri­tion. To allow for this process to take place, dietary re­quirements, including those for energy, protein, iron and cal­cium, increase. If dietary intake is insufficient, anemia and micronutrient deficien­cies will emerge; while deficiencies that are treated may allow for catch-up growth. Because there is limited data on interventions for adolescent stunting, the needs of this unique age group are not sufficiently addressed. Different aspects of adolescent undernutrition and stunting are discussed, and directions for future research are highlighted.

1. STUNTING OF GROWTH IN DEVELOPING COUNTRIES

A. Prentice1. 1MRC UNIT The Gambia at London School of Hygiene & Tropical Medicine, Nutrition, Keneba, The Gambia.

Stunting of Growth in Developing Countries Andrew M. Prentice, MRCG@LSHTM, Keneba, The Gambia

This year’s summary of the key publications in 2018 on stunting in LMIC countries covers a broad remit. The most important publications where the twin papers from the WASH Benefits Trials in Bangladesh and Kenya. These large and very well conducted cluster-randomised trials found a small benefit of improved infant and young child feeding (IYCF) but no benefit of improved water, sanitation and hygiene (WASH). These profoundly disappointing results have been covered elsewhere in the programme. The results from the SHINE Trial from Zimbabwe were published after the window for selection of YearBook abstracts had closed, but found almost identical results. A trial from The Gambia tested the impact of physician-prescribed lipid-based nutrient supplements given to sick children presenting to clinic. There was no benefit on the primary outcome of repeat clinic visits and only a very small effect on linear growth. In a post hoc analysis there was an increase in infections in the first 3 weeks of micronutrient supplementation which might be due to iron. Trial protocols for interesting interventions were published in the year and these will be summarised.

Plenary lecture on Nutrition and Childhood Obesity provides two from three topics with abstracts, as follows:

1. CHILDHOOD OBESITY-CLINICAL CHARACTERISTICS

G. Martos-Moreno1, J. Argente2. 1Hospital Infantil Universitario Niño Jesús. IIS La Princesa. Universidad Autónoma de Madrid. ISCIII, Departments of Pediatrics and Pediatric Endocrinology. CIBEROBN, Madrid, Spain. 2Hospital Infantil Universitario Niño Jesús. IIS La Princesa. Universidad Autónoma de Madrid. ISCIII. IMDEA food institute, Departments of Pediatrics and Pediatric Endocrinology. CIBEROBN, Madrid, Spain.

Background: The current understanding of pathophysiological and molecular basis of obesity has led to the idea that there is not a single type of this disease, but several types of "obesities", which need to be investigated and properly diagnosed in order optimize patients´ care, singularly during childhood.

Body: Throughout the talk we will try to summarize the classification of the different etiologies of obesity in childhood and adolescence according to their etiology; highlighting the most representative diagnoses in each group. In addition, we will remark the most important familial and personal background elements to be collected in childhood obesity focused clinical records, as well as the most significant characteristics that should be seeked for when performing physical examination in these patients. Finally, on the basis of the increasing number and genetic heterogeneity of multiple cases of early onset obesity, a few of which are tributary for specific treatments either available or under development, a diagnostic strategy will be proposed.

Conclusion: Current management of chidhood obesity, particularly of early onset obesity determines the need for accurate and patient focused background records and clinical examination. The identification of an increasing number of cases of obesity with a genetic origin and the investigational efforts in the development of drugs for the treatment of specific forms of obesity determine the need for more accurate etiological diagnosis of the different types of obesities.

1. GENETIC VARIANTS IN CHILDREN WITH NON-SYNDROMIC EARLY-ONSET OBESITY (EOO): CHARACTERIZATION AND TREATMENT

J. Argente1, G. Martos-Moreno1, L. Pérez-Jurado2. 1Universidad Autónoma de Madrid. University Hospital Niño Jesús, Pediatrics & Pediatric Endocrinology, Madrid, Spain. 2Universitat Pompeu Fabra, Genetics, Barcelona, Spain.

TITLE: Identification of rare genetic variants in patients with non-syndromic early-onset obesity (EOO): Characterization and treatment. institutions: Universidad Autónoma de Madrid (Department of Pediatrics). Hospital Infantil Universitario Niño Jesús (Departments of Pediatrics & Pediatric Endocrinology). CIBER de obesidad y nutrición (CIBEROBN). Instituto de Salud Carlos III and Instituto IMDEA. Madrid, Spain. Background: Obesity is a highly heterogeneous disorder at both the clinical and molecular level. It also has a high heritability. At least 10 genes have been reported to cause monogenic severe obesity and these are mainly inherited in a recessive manner. More candidate genes have been identified in associated studies, but more information is needed regarding their direct effect on obesity. We aimed to determine the contribution to severe early-onset obesity (BMI > +3SDS, onset < 3years) of rare point mutations in selected candidate genes. Results: A pooled DNA sequencing approach was used to screen 15 genes that are possible candidates for association with obesity in a cohort of 480 patients and 480 controls. The genes screened included: 1) those reported to be altered in patients with obesity (LEP, LEPR, MC3R, MC4R, PCSK1, NTRK2 and SIM1) and 2) those with SNPs associated to obesity by GWAS (BDNF, FTO, NEGR1, GHSR, ADRB3, PPARG, PCSK2, PCSK1 and TMEM18A). Our focus was on very rare variants that were found in a single or few individuals in our cohort. Of the 15 genes studied, 7 (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) rare variants were differentially represented in patients and controls. Thirty rare variants in these 7 genes were found in 35 patients and 5 were found in 6 controls (p<0.0001). The difference in probable pathogenic variants (15 variants in 17 patients and only 1 variant in a single control) was also significant (p=0.0001). All variants were single allele changes, with no individual carrying more than one variant. Conclusion: We found a higher burden of rare and probable pathogenic heterozygous variants in several candidate genes in patients with severe early-onset obesity compared to controls. These results emphasize the importance of the melanocortin pathway (including MC3R). They also highlight other genes that may carry highly penetrant obesogenic single allele variants such as SIM1, PPARG and BDNF.

Session on What is the Link Between Nutrition and Growth provides three topics as follows:

1. STUNTING OF GROWTH IN THE FIRST FIVE YEARS OF LIFE: CAUSES AND NUTRITIONAL INTERVENTIONS

R. Black1. 1Johns Hopkins University Bloomberg School of Public Health, International Health, Baltimore, USA.

Stunting of linear growth, a highly prevalent problem in children of low- and middle-income countries, is the result of the exposure of the fetus and/or young child to nutritional deficiencies and infectious diseases. Maternal undernutrition results in fetal growth restriction, and infectious diseases in pregnancy can result in preterm delivery. Both of these conditions are important contributors to stunting in early childhood, albeit their relative contribution varies by world region. After birth, growth faltering may begin at 3-5 months of life and becomes more prominent from 6 to 18 months. During this time, the young child is exposed to many infectious diseases, such as diarrhea, that have an adverse effect on growth. There is also increasing evidence that frequent ingestion of microorganisms results in damage to the small intestine. The resulting condition, referred to as environmental enteric dysfunction, even without clinical symptoms, may cause growth faltering. The complementary foods that the child receives in addition to breast milk are often inadequate in nutrients and energy, negatively affecting growth. Harmful exposure during pregnancy and the first 2 years of life, a critical period for growth and development, has led to a programmatic focus on this "1,000 days" in the life cycle. Dietary interventions, including nutrition education and for undernourished women provision of food supplements during pregnancy, result in improvements in fetal growth that position the newborn for healthier growth. Interventions in the first 2 years of life include promotion of exclusive breastfeeding for the first 6 months of life and continued breastfeeding for at least the first 2 years, nutritional counseling to assure adequate complementary feeding, and, if necessary in food insecure areas, the provision of supplemental food to be given to the child. Evidence shows that each of the interventions has a beneficial effect on the growth of the young child, yet that the effect is modest in relation to the degree of stunting observed in these underprivileged populations. Nevertheless, in recent years, reductions in the prevalence of stunting in some low-income countries show that substantial improvements are possible as a result of socioeconomic changes along with specific infection control and dietary interventions.

1. STUNTING IS NOT A GOOD INDICATOR OF UNDERNUTRITION

M. Hermanussen1, B. Bogin2, C. Scheffler3. 1University of Kiel, Pediatrics, 24340 Altenhof, Germany. 2Exercise & Health Sciences, School of Sport, Loughborough, United Kingdom. 3University of Potsdam, Human Biology, 14469 Potsdam, Germany. Abstract Text

Background and aims: In the modern nutrition literature, the terms "stunting" and "undernutrition" are usually linked and synonymously used. Yet already during and after World War I, scientific evidence had accumulated that such a link is not valid. We aimed to further scrutinize the validity of this association. Methods: We re-analyzed fat tissue thickness and height in 5019 children and adolescents from Kolkata/India, and from 1715 Indonesian children, with up to 53% “stunted” children in the respective cohorts. Results: The data do not support current concepts defining chronic nutrient deficiency by measures of body height. Discussion: In view of evidence from social mammals, and historic data from several European populations we instead, strongly consider social-driven competitive growth strategies that regulate body height by other than physical biological factors. We suggest identifying growth inhibition caused by malnutrition by the combination of measurement of height along with indicators of energy balance such as triceps and subscapular skinfolds. This contribution intends to stimulate the debate why apparently healthy and well-nourished children raised in remote areas of former European colonies should grow according to references constructed for populations raised under distinctly different cultural, political, economic, and psychosocial circumstances. The data presented seriously question the inappropriate use of so-called global growth standards for child growth. Conclusions: We oppose the current misinterpretation of short stature as a proxy indicator for malnutrition. Malnutrition leads to stunting, but stunting by itself does not indicate malnutrition.

1. WHY OBESITY INTERVENE WITH ACHIEVING GROWTH POTENTIAL

G. Gat-Yablonski1, M. Masarwi2, R. Shamir3, M. Phillip1. 1Schneider Children's Medical Center, Institute for Endocrinology and Diabetes, Petach Tikva, Israel. 2Tel Aviv University, Endocrinology, Tel Aviv, Israel. 3Schneider Children's Medical Center, Institute of Gastroenterology- Nutrition and Liver Diseases, Petach Tikva, Israel.

Catch-up growth (CUG) in childhood is defined as periods of growth acceleration, after the resolution of growth attenuation causes, bringing the children back to their original growth trajectory. Sometimes, however, CUG is incomplete, leading to permanent growth deficit and short stature. In this talk I will present our studies aiming to investigate the mechanisms that limit nutritional-CUG. Specifically, we focused on the crosstalk between leptin, increased by re-feeding, and sex hormones, which increase with age. I will describe our recent studies on young male Sprague Dawley rats fed ad libitum or subjected to 10/36 days of 40% food restriction followed by 90–120 days of re-feeding. In vitro studies were performed on ATDC5 cells. We found that CUG was complete in body weight and humerus length in animals that were food-restricted for 10 days but not for those food-restricted for 36 days. In vitro studies showed that leptin significantly increased aromatase gene expression and protein level as well as the expression of estrogen and leptin receptors in a dose- and time-dependent manner. The effect of leptin on aromatase was direct and was mediated through the MAPK/Erk, STAT3 and PI3K pathways. The crosstalk between leptin and aromatase in the growth plate suggests that re-feeding during puberty may lead to increased estrogen level and activity, and consequently, irreversible premature epiphyseal growth plate closure. These results may have important implications for the development of novel treatment strategies for short stature in children.

In the session of Nutrition and Disease, it provides three topics as follows:

1. GENETIC SYNDROMES ASSOCIATED WITH FEEDING PROBLEMS (SILVER-RUSSEL SYNDROME, HETEROZYGOUS IGF1R MUTATIONS OR DELETIONS, NOONAN SYNDROME)

M. Walenkamp1. 1Emma children's Hospital- Amsterdam UMC- Vrije Universiteit Amsterdam- Amsterdam- the Netherlands, Pediatrics, Amsterdam, The Netherlands.

Patients presenting with short stature, in whom a genetic cause is considered, a detailed history of the feeding pattern contributes to identify the underlying disease. Feeding problems are described as a well known feature in many syndromes, in particular in Silver-Russell syndrome (SRS), Bloom syndrome (BS) and IGF-I receptor mutations or deletions.

Feeding problems include poor sucking, vomiting, gastro-oesophageal reflux, poor appetite, slow feeding, oromotor issues and denial of food and result in low caloric intake and failure to thrive. Nasogastric tube feeding or percutaneous endoscopic gastrostomy is necessary to prevent severe weight loss in some cases.

Recently we evaluated a cohort of children with a defect of the IGF-I receptor. Typical features were born small for gestational age, short stature, small head circumference and increased IGF-I levels. 15 out of 19 cases experienced feeding problems. In patients with this fenotype IGF1R analysis should be considered.

The Nethine-Harbison clinical scoring system was developed to identify patients with SRS. The score includes birth size, height, relative macrocephaly at birth, protruding forehead, body asymmetrie and feeding difficulties. In the consensus statement (Wakeling et al 2016) recommendations for feeding and nutritional support are published. These patients benefit from growth hormone treatment regarding body composition, psychomotor development and appetite.

In children with BS significant feeding problems occur with apparent lack of interest in eating, gastroesophageal reflux and excessive vomiting. Children with BS show severe pre- and postnatal growth failure. The typical butterfly rash on the face which exacerbates by sun is not present during infancy but develops as they age. It is important to recognize this chromosomal instability syndrome because of a greatly increased risk of early onset of cancer.

1. NUTRITION IN GLUTEN RELATED DISORDERS

C. Koninckx1. 1La Fe University Hospital, Pediatric Gastroenterology Hepatology and Nutrition Unit, Valencia, Spain.

Coeliac disease is a permanent intolerance to gluten and related prolamins which develops in genetically predisposed individuals. Gluten is the main structural protein of wheat with equivalent toxic proteins found in rye and barley.In coeliac patients, gluten causes a systemic autoimmune disease and results in the development of intestinal and extra-intestinal manifestations.

Several epidemiological studies have estimated a prevalence of one case per 130-400 individuals in the general population, with lower prevalence in Asian countries.

The only currently available treatment for CD is a life-long strict adherence to a gluten-free diet ( GFD), which means to avoid consumption of wheat, barley and rye. Oats is considered to be tolerated by a majority of coeliac patients although their role in CD pathogenesis is still a matter of debate

Challenges for a strict adherence to a GFD:

Compliance with a gluten-free diet is very difficult in practice due to the widespread presence of gluten in Western diets.

Non Voluntary / Occult transgressions are frequently due to eating out and specially related to school catering , holidays , summer camps , social life ( birth day parties, etc.. ); home confusing labeling of food products as well as contamination issues may be a real challenge for strict avoidance. Voluntary transgressions are frequently observed in adolescents, young children, adults not accepting the diagnosis or considering a GFD has a negative impact on their Quality of Life.

Also the higher costs of GF foods as compared to their gluten containing counter parts may hamper adherence

How to monitor adherence

CD specific serological markers are not reliable to detect occasional or small dietary transgressions. Even so no evident clinical symptoms have to be expected for occasional gluten intake due to sporadic voluntary non adherence or to inadvertently transgression because of, among other causes, contamination of food products.

The paucity of monitoring options means that serology remains widely employed as a marker of intestinal damage even though it correlates poorly with villous atrophy. In contrast with its excellent sensitivity for disease screening, serology does not detect small amounts of gluten ingestion and the sensitivity of tTG IgA to detect persistent villous atrophy is typically less than 50%, although DGP antibodies may perform better.

Recently a new method for the detection of gluten inmuno peptides in faeces and in urine by means of a highly sensitive anti-gliadin 33-mer MoAb has turned out as a powerful tool for recent dietary transgressions.

Non Coeliac Gluten/wheat Sensitivity ( NCGS)

Besides CD, there are cases of gluten reactions, generally in the adult population, in which neither allergic nor autoimmune mechanisms can be identified. We define as non-celiac GS when individuals experience symptoms when eating gluten-containing products which improve on a GFD. NCGS is a condition distinct from CD as the small intestine is usually normal and no positivity for anti-tTG autoantibodies can be detected . As NCGS can be transitory experts recommend the gluten-free diet should be followed for a given period, eg, 12 to 24 months, before testing gluten tolerance again. Based on severity of symptoms, some gluten sensitive patients without celiac disease may choose to follow a gluten-free diet indefinitely. Recent studies raise the possibility that in addition to gluten, other grains’ components, including amylase trypsin inhibitors (ATIs) and fermentable short-chain carbohydrates (FODMAPs) may trigger symptoms in GS. Oats can be considered safe also for NCGS subjects due to their lower prolamin content[61] and for their lower ATI innate immune stimulatory activity . Whether it is gluten and/or other proteins in wheat that are responsible for the development of symptoms in NCGS patients remains to be determined. Therefor the term non-celiac wheat sensitivity (NCWS) is suggested by some authors as more appropriate than NCGS .

1. NUTRITION AND GROWTH IN INFLAMMATORY BOWEL DISEASE

R. Shamir1. 1Chairman- Institute for Gastroenterology- Nutrition and Liver Disease- Schneider Children's Medical Center- Professor of Pediatrics- Sackler Faculty of Medicine- Tel Aviv University- Israel, Institute for Gastroenterology- Nutrition and Liver Disease, Tel Aviv, Israel.

Nutrition in Inflammatory Bowel Diseases

Raanan Shamir, MD

Chairman, Institute for Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center, Professor of Pediatrics, Sackler Faculty of Medicine, Tel Aviv University, Israel

Inflammatory bowel disease (IBD) is a term used to describe a group of diseases that includes Crohn's disease (CD) and ulcerative colitis (UC). Malnutrition and nutrient deficiencies are common in IBD and more so in CD. For decades, enteral feeding has been used as part of the nutritional therapy of IBD. Exclusive enteral nutrition (EEN) which is defined as the provision of 100% of an individuals' nutritional requirements from a liquid nutritional formula either orally or via a feeding tube for about 8 weeks, is considered as efficacious as steroids in the induction of remission for luminal Crohn’s disease in children and adolescents. The reason is not clear, but possible explanations include nutritional improvement effects, reduced antigenic load, bowel rest (elemental diet), provision of trophic amino acids, modification of gut flora, reduced gut permeability, reduced mucosal inflammation and supplementation of antioxidants. In a recent meta-analysis, in addition to a similar effect as steroids on induction of remission, EEN was shown to be more efficacious than steroids in inducing mucosal healing irrespective of disease phenotype. EEN can be given orally or via a nasogastric tube and repeated courses are efficacious though in a lesser extent than the first time. Currently, EEN is recommended as the first choice for inducing remission in pediatric patients with luminal CD.

Growth retardation is seen in up to 40% of children with (IBD), and as a result it may have long term effects on final adult height. Etiology may include undernutrition, metabolic dysregulation, inflammatory impact on hormonal growth axis and the effect of drugs such as glucocorticoids. Control of disease activity and minimizing the need for corticosteroid therapy are necessary measures in order to facilitate normal growth. Nutrition has a role in the prevention of growth retardation, however, it has an excellent effect on weight but less so on height.

Diet is important in the pathogenesis of IBD and there is accumulating evidence for the role of specific diets such as the CD Exclusion diet and the CD treat in induction of remission.

On the session entitled Food Allergy – Current Opinions of Prevention and Nutritional Management, we got four presentation as follows:

1. INTRODUCTION OF POTENTIALLY ALLERGENIC FOODS: SHOULD THE GUIDELINES BE THE SAME IN ALL COUNTRIES?

M. Fewtrell1. 1UCL Great Ormond Street Institute of Child Health, Childhood Nutrition Research Centre, London, United Kingdom.

Many countries have noted increasing rates of food allergy in recent years despite advice to parents to delay or avoid introducing allergenic foods to their infants. This has led to a change in focus, based on the concept of inducing tolerance in infants by oral exposure to food allergens. Data from cohort studies suggest that the risk of later allergy, including food allergy, may be increased if the introduction of allergenic foods is delayed; however, reverse causality is impossible to exclude. A number of randomised trials have now been conducted, with others ongoing, examining the effects of introducing allergenic foods to infants at different ages on the development of food allergy. These trials vary in a number of respects which are relevant when considering how their findings should be translated into practice: they were conducted in different populations (mostly from Western countries), at different risk of allergy, using different allergens in different forms and amounts, and with different ages at introduction.

Whilst there is now general agreement that the introduction of food allergens does not need to be delayed, and that they can be treated in the same way as other complementary foods, specific guidance must be tailored for the population for whom advice is intended. Important factors to consider include the foods and food allergens typically consumed by the population, the prevalence of food allergy, genetic and environmental factors that may influence sensitisation and allergy, and the individual infant’s risk of allergy. The healthcare system and available resources, including availability of paediatric allergists are also important. Thus specific guidance on the introduction of allergenic foods should not be the same in all countries and settings.

1. IS THERE CONSENSUS ON THE USE OF HYDROLYZED FORMULAS FOR ALLERGY PREVENTION?

S. Kolacek1. 1Head of department, Referral Center for Pediatric Gastroenterology and Nutrition- Children's Hospital Zagreb, Zagreb, Croatia.

IS THERE CONSENSUS ON THE USE OF HYDROLYZED FORMULAS FOR ALLERGY PREVENTION?

Allergic disorders comprising of eczema, food allergy, allergic rhino-conjunctivitis and asthma, are among the most common chronic non-communicable diseases in children. They are associated with significant morbidity and rate of hospitalization, decreased quality of life of the whole family, and are imposing tremendous costs on the health system. A preventive approach is therefore of great interest, and various preventive measures have been described. In early infancy, particularly in the first 3 months, the increased intestinal permeability coupled with the immaturity of the mucosal immune system enable access of food macromolecules across the mucosal barrier into the systemic circulation, raising the risk for the development of food allergy. This is the “physiological background” for a hypothesis on the potential preventive effect of feeding non-breast-fed infants at increased risk for allergy with the infant formulas in which proteins are hydrolyzed into the smaller, hence, potentially less allergenic molecules. As for the sources, main cow’s milk proteins – whey and casein - are used in the great majority of hydrolyzed products. According to the extent of hydrolysis, formulas are divided into the extensively hydrolyzed (eHF) comprising of very small peptides with molecular weight below 3 kDa, and partially hydrolyzed (pHF) consisting of peptides mostly below 5 kDa. The eHF have been used for many decades in the treatment of infants with cow’s milk protein allergy but also in prevention of allergy, while the potential role of pHF is mainly in prevention. Besides on the molecular weight, the studies have shown that their allergenicity depends also on the method of hydrolysis and the protein source. There have been many studies comparing hydrolyzed formulas in respect to their molecular weight and also protein source. The results were summarized in several meta-analyses and were objects for several systematic reviews. However, the results obtained are not unequivocal, and therefore the use of hydrolyzed formulas for allergy prevention is still a matter of debate. In the present lecture, the background for the potential role of hydrolyzed formulas will be introduced, a distinction in respect to the degree of hydrolyzes and protein sources will be presented, and results of the most important high quality studies and meta-analyses will be shown. Based on that, the current recommendations for the preventive use of hydrolyzed formulas in the high risk infants and in the general population will be discussed.

1. TREATMENT (DESENSITIZATION) OF FOOD ALLERGIES

C. Dupont1. 1Paris Descartes University, Hospital Necker, Paris, France. Purpose:

Food allergies are increasing and severely impact the quality of life of the children and their family. Until now, the standard treatment for food allergies was strict avoidance i.e. elimination of the allergenic food(s) from the patient’s diet to prevent allergic reactions. Avoidance remains the mainstream attitude, but recent progress was made leading to new therapeutic options for food allergic chidren. The latter are mainly the so-called “immunotherapy”, according to which allergic children are in contact with the offending food with the goal of a progressive desensitization to this food. Immunotherapy is a promising alternative to traditional avoidance. According to the route of contact between the patient and the allergen, interventions are labeled oral immunotherapy (OIT), sublingual immunotherapy (SLIT) and epicutaneous immunotherapy (EPIT). OIT and EPIT are currently in a process of pharmaceutical development by two different companies. This presentation describes the pros and cons of all methods.

1. GROWTH IN CHILDREN WITH FOOD ALLERGY

R. Meyer1. 1Imperial College London, Paediatrics, London, United Kingdom.

Poor growth has been recognised by all of the current guidelines on food allergy as a symptom to consider with other atopic symptoms and a factor of concern for later health. To date, a low weight for height is more commonly reported than a low weight for age or weight for height. The mainstay of management of food allergies is dietary elimination. During early childhood, this may entail the elimination of nutrients essential for growth, including cow's milk. Poor growth has in the past mainly been blamed on dietary elimination and insufficient energy, protein intake and inappropriate replacement of nutrients that have been eliminated. However, data does not always support this notion that an energy deficit is at the heart of the problem. Although vitamins and mineral deficiencies are commonly reported, the association with growth is poorly studied in food allergies. Similarly, the role of atopic co-morbidities and ongoing inflammation is only now starting to be considered in the pathophysiology of disordered growth in children with food allergy. This presentation aims to provide an overview on the prevalence of undernutrition in food allergy and factors that need to be considered.

Related to the session on Early Microbiota Imprinting, we could only access one topic with an abstract from the four topics, as follows:

GUT MICROBIOTA MODIFICATIONS. A 2019 UP-DATE

H. Szajewska1. 1The Medical University od Warsaw, Department of Paediatrics, Warsaw, Poland.

The human microbiota is defined as organisms (bacteria, viruses, or eukaryotes) that are present in an environmental habitat, but mainly in the gut. A large number of studies indicated that alteration in gut microbiota composition and function, particularly in the early life, plays crucial role in health and disease. With the growing recognition of the role of gut microbiota, it is clear that gut microbiota may be a target for improving outcomes in subjects affected or at risk for certain diseases. To date, modification of gut microbiota via the provision of probiotics is the most extensively studied strategy. However, some recent studies questioned probiotic health benefits. New data are available on prebiotics, including human milk oligosaccharides, synbiotics, and postbiotics. This presentation will briefly discuss their effects on health outcomes and current controversies. Moreover, the effects of the administration of antibiotics in early life on chronic diseases, including allergies, overweight/obesity will be discussed. Gaining a better understanding of how microbiota is linked to health and disease is needed to develop next-generation modulators of the gut microbiota. The latter, once developed, need to be evaluated in well-designed and executed randomized controlled trials with clinically important outcome measures

As conclusions, I found that the 6th Nutrition and Growth International Conference 2019 is really beneficial in enriching and updating my current knowledge and experiences. Hope I can still follow the next year international conference in London.

Best regards,

Prof. Dr. dr. Saptawati Bardosono, MSc