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Growth characteristics during periods of early developmental plasticity are linked with later health outcomes and with disease risks. Infant growth is modulated by genetic and exogenous factors including nutrition. We try to explore their underlying mechanisms using targeted metabolomic profiling of small molecules in biological samples using high-performance liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) to quantify hundreds of molecules in small biosamples, e.g., 50 µL plasma. In the large German LISA birth cohort study, cord blood lysophosphatidylcholines and fatty acids were closely associated with infant birth weight, with a nonsignificant trend towards an association with infant weight gain and later BMI. Studies in infants randomized to different protein intakes in the European CHOP Study show conventional high protein intakes to markedly increase plasma-indispensable amino acids (AA), particularly branched-chain AA (BCAA), while exceeding the infant's capacity of BCAA breakdown, and an increase in the dispensable AA tyrosine previously associated with insulin resistance. In a path model analysis of the relationship of infant plasma AA, growth factors, and infant growth, AA were generally found to induce a stronger response of insulin than IGF-I although effects of individual AA were very different. We conclude that targeted improvement in nutrient supply in pregnancy and infancy may offer large opportunities for promoting desirable child growth patterns and long-term health., (© 2018 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel.)

The complementary feeding period is a short transitional period from breastfeeding and formula feeding to family foods. Timing, quantity, and quality are implied to impact growth and obesity risk. We summarized the literature and analyzed data of monthly 3-day food diaries of >1,000 children from 5 European countries in the first 2 years of life, which were collected as part of the prospective European Childhood Obesity Project (CHOP Study). Formula-fed children started complementary food approximately 2 weeks earlier than breastfed children, and almost 40% of them at or before 4 months of age. While introduction of solids between 4 and 6 months or after 6 months does not seem to impact growth and later obesity risk, solids before 4 months of age increased the risk. There are indications that this is especially problematic for formula-fed children. During the complementary feeding period, fat intake decreases, and protein and carbohydrate intakes increase. Protein intake often exceeds European recommendations from 9 months onwards. However, the role of macronutrients during complementary feeding in growth and metabolism needs further clarification. Findings on the role of responsive feeding or baby-led feeding during complementary feeding in growth are not conclusive. In summary, while introduction of complementary foods before 4 months of age should be avoided, the impact of the quality of complementary food on short-term growth and later obesity risk has to be elucidated further., (© 2018 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel.)

Background/aims: Dietary factors can modify calciuria. We aim to investigate urinary calcium excretion in healthy infants according to their protein., Methods: Secondary data analysis from a randomized clinical trial where healthy term infants were randomized after birth to a higher (HP) or lower (LP) protein content formula that was consumed until age 1 year. A non-randomized group of breastfed (BF) infants was used for reference. Anthropometry, dietary intakes and calciuria (calcium/creatinine ratios) from spot urine samples were assessed at ages 3 and 6 months. At 6 months, the kidney volumes were assessed using ultrasonography, and the serum urea and creatinine levels were determined., Results: BF infants showed the highest calciuria levels, followed by the HP and the LP groups (p < 0.001 for all comparisons). Either protein intakes or formula types modulated the calciuria in linear regression models adjusted for other influencing dietary factors. The usual cut-off values classified 37.8% (BF), 16.8% (HP) and 4.9% (LP) of the infants as hypercalciuric., Conclusions: Feeding types during the first months of life affect calciuria, with BF infants presenting the highest levels. We propose new cut-off values, based on feeding types, to prevent the overestimation in hypercalciuria diagnoses among BF infants., (© 2017 S. Karger AG, Basel.)

The Power of Programming conference 2016 at Ludwig-Maximilians-Universität Munich brought together about 600 researchers and other stakeholders from around the world who reviewed the recent evidence on the lasting health impact of environment and nutrition during early life, from pre-pregnancy to early childhood. The conference was hosted by the Early Nutrition Project, a multidisciplinary research collaboration funded by the European Commission with collaborating researchers from 35 institutions in 15 countries in Europe, the United States and Australia. The project explores the early origins of obesity, adiposity and associated non-communicable diseases, underlying mechanisms and opportunities for prevention. The project also proactively supports translational application of research findings. In fact, some existing evidence has already been rapidly adopted into policy, regulatory standards and practice. Further, broad dissemination of findings is achieved through the established digital eLearning platform of the Early Nutrition eAcademy, video clip-based learning and graphically supported messaging to consumers. The project demonstrated powerful effects of early metabolic programming on later health. Compared to other common prevention strategies, modifying risk trajectories in early life can achieve a much larger risk reduction and be more cost-effective. While some effective prevention strategies have been promptly implemented in policy and guidelines, legislation and practice, in other areas, the uptake is limited by a paucity of quality human intervention trials and insufficient evaluation of the feasibility of implementation and econometric impact. This needs to be strengthened by future collaborative research work., (© 2017 S. Karger AG, Basel.)

There is growing evidence of long-term effects of early dietary intervention in infancy on later obesity risk. Many studies showed reduced risk of obesity with breastfeeding in infancy, which could be related to the reduced protein intake with human milk compared to infant formula. In a randomized controlled trial (Childhood Obesity Project), we were able to show that infant formula with reduced protein content results in lower BMI both at 2 and 6 years. These effects seem to be mediated mainly by branched-chain amino acids which stimulate the insulin-like growth factor (IGF)-1 axis and insulin release. In this trial, we also showed an influence of high-protein diet on larger kidney size, which seems to be partly explained by a significant effect of free IGF-1 on kidney volume. The IGF-1 axis was shown to regulate early growth, adipose tissue differentiation and early adipogenesis in animals and in humans. Leptin and adiponectin can also be regarded as important endocrine regulators of obesity. These markers were tested in observational studies. Leptin seems to be closely correlated with BMI but changes in adiponectin require further exploration. Still, there is a lack of good data or some results are contradictory to indicate the role of either leptin or adiponectin in infancy for determining later obesity risk., (© 2016 Nestec Ltd., Vevey/S. Karger AG, Basel.)

Breastfeeding induces a different metabolic and endocrine response than feeding conventional infant formula, and it has also been associated with slower weight gain and reduced disease risk in later life. The underlying programming mechanisms remain to be explored. Breastfeeding has been reported to induce lower levels of insulin, insulin-like growth factor-1 and some amino acids (AAs) than formula feeding. In the Childhood Obesity Project (CHOP), infants fed a conventional protein-rich formula had a higher BMI at 2 and 6 years than those fed a protein-reduced formula. At 6 months, higher protein intakes induced increased plasma concentrations of branched-chain AAs (BCAAs) and their oxidation products, short-chain acylcarnitines. With increasing BCAA levels, these short-chain acylcarnitines increased proportionally only until a break point was reached, after which BCAAs seemed to escape their degradation. The resulting marked elevation in BCAA levels with high-protein (HP) intakes appears to contribute to increased insulin levels and to affect β-oxidation of fatty acids. The ratios of long-chain acylcarnitines to free carnitine decreased in infants who received a HP formula, which indicates a reduced initiation of β-oxidation. We conclude that HP intakes inducing high BCAA plasma levels may inhibit fat oxidation and thereby enhance body fat deposition and adiposity., (© 2016 Nestec Ltd., Vevey/S. Karger AG, Basel.)

Growth and development are central characteristics of childhood. Deviations from normal growth can indicate serious health challenges. The adverse impact of early growth faltering and malnutrition on later health has long been known. In contrast, the impact of rapid early weight and body fat gain on programming of later disease risk have only recently received increased attention. Numerous observational studies related diet in early childhood and rapid early growth to the risk of later obesity and associated disorders. Causality was confirmed in a large, double-blind randomised trial testing the 'Early Protein Hypothesis'. In this trial we found that attenuation of protein supply in infancy normalized early growth and markedly reduced obesity prevalence in early school age. These results indicate the need to describe and analyse growth patterns and their regulation through diet in more detail and to characterize the underlying metabolic and epigenetic mechanisms, given the potential major relevance for public health and policy. Better understanding of growth patterns and their regulation could have major benefits for the promotion of public health, consumer-orientated nutrition recommendations, and the development of improved food products for specific target populations., (© 2014 S. Karger AG, Basel.)

Background: Idiopathic hypercalciuria (IHC), i.e. an elevated urinary calcium excretion without concomitant hypercalcemia, is a common disorder in children and can have a range of urinary clinical presentations and decreased bone mineral density (BMD)., Aim: To assess the effect of IHC on bone mineral content in children without urological symptoms., Methods: Calcium excretion, BMD (by dual-energy X-ray absorptiometry), and anthropometry were assessed in 175 seven-year-old children who were classified as IHC or controls. Calcium intake and physical activity were measured as confounding factors., Results: The prevalence of IHC was 17.7%. Both groups (controls and IHC) showed similar baseline characteristics in terms of their anthropometry, gender distribution, and protein and calcium dietary intakes as well as physical activity scores. Urinary calciuria was independent of the calcium dietary intake and anthropometry. BMD correlated with anthropometry and physical activity but not with calcium dietary intake. IHC children had lower whole-body BMD z-scores compared to controls. The role of IHC in reducing the whole-body BMD z-score was still significant even when anthropometry, physical activity, and calcium intake were included as confounders in multivariate analyses., Conclusions: The prevalence of IHC in this population of 7-year-old children was about 17%. IHC diagnosis was associated with lower BMD z-scores and osteopenia in 22% of them., (© 2014 S. Karger AG, Basel.)

Background: Across Europe, poor health behaviours are associated with increased risks of non-communicable diseases. There is particular concern about young women, children and families, not least as health behaviours operating before and during pregnancy and in early postnatal life may have profound long-term consequences for children's health. Using findings drawn from 7 European countries, we aimed to identify barriers to the implementation and uptake of dietary and physical activity recommendations, and to consider how best to achieve changes in mothers' behaviours and thereby improve the adoption of health recommendations. Six studies across the 7 countries were used for this narrative synthesis of findings., Key Messages: A woman's education has a strong influence on her own and her children's health behaviours. Women's diets vary across ethnic groups and according to number of children, but psychological factors, such as self-efficacy and sense of control, which may be amenable to modification, are powerful, too, particularly in women with lower educational attainment. Maternal influences on children's behaviours are strong. Differences exist in infant feeding across countries, and there are apparent urban/rural differences in children's diets and physical activity., Conclusions: Interventions are needed before, as well as during, pregnancy to improve the diets of families with young children. Interventions to address psychological barriers to eating well and being more active are indicated., (© 2014 S. Karger AG, Basel.)

At The Power of Programming 2014 Conference, researchers from multiple disciplines presented and discussed the effects of early nutrition and other environmental cues during the first thousand days of life and beyond on the lifelong risk of noncommunicable diseases. This paper aims to summarize the concepts and some of the first achievements of the EarlyNutrition research project that initiated the conference. The EarlyNutrition consortium is a multinational, multidisciplinary research collaboration of researchers from Europe, the USA, and Australia. A focus is placed on exploration of the developmental origins of obesity, adiposity, and related health outcomes. Here we report on the first findings of experimental approaches, cohort studies, randomized clinical trials, and systematic reviews of current information, as well as position papers, which have all been developed with the involvement of project partners. We conclude that the EarlyNutrition project has successfully established itself during the first 2 project years as a very strong platform for collaborative research on early programming effects. The first results, available already at this early stage of the project, point to great opportunities for health prevention strategies via the implementation of dietary and lifestyle modifications, with large effect sizes. Further results are expected which should support improved recommendations and related policies for optimized nutrition and lifestyle choices before and during pregnancy, in infancy, and in early childhood., (© 2014 S. Karger AG, Basel.)

Background: Despite the growing interest in the early-origins-of-later-disease hypothesis, little is known about the metabolic underpinnings linking infant weight gain and childhood obesity., Objective: To discover biomarkers reflective of weight change in the first 6 months and overweight/obesity at age 6 years via a targeted metabolomics approach., Design: This analysis comprised 726 infants from a European multicenter randomized trial (Childhood Obesity Programme, CHOP) for whom plasma blood samples at age 6 months and anthropometric data up to the age of 6 years were available. 'Rapid growth' was defined as a positive difference in weight within the first 6 months of life standardized to WHO growth standards. Weight change was regressed on each of 168 metabolites (acylcarnitines, lysophosphatidylcholines, sphingomyelins, and amino acids). Metabolites significant after Bonferroni's correction were tested as predictors of later overweight/obesity., Results: Among the overall 19 significant metabolites, 4 were associated with rapid growth and 15 were associated with a less-than-ideal weight change. After adjusting for feeding group, only the lysophosphatidylcholine LPCaC14:0 remained significantly associated with rapid weight gain (β = 0.18). Only LPCaC14:0 at age 6 months was predictive of overweight/obesity at age 6 years (OR 1.33; 95% CI 1.04-1.69)., Conclusion: LPCa14:0 is strongly related to rapid growth in infancy and childhood overweight/obesity. This suggests that LPCaC14:0 levels may represent a metabolically programmed effect of infant weight gain on the later obesity risk. However, these results require confirmation by independent cohorts., (© 2014 S. Karger AG, Basel.)

Health and nutrition modulate postnatal growth. The availability of amino acids and energy, and insulin and insulin-like growth factor-I (IGF-I) regulates early growth through the mTOR pathway. Amino acids and glucose also stimulate the secretion of IGF-I and insulin. Postnatal growth induces lasting, programming effects on later body size and adiposity in animals and in human observational studies. Rapid weight gain in infancy and the first 2 years was shown to predict increased obesity risk in childhood and adulthood. Breastfeeding leads to lesser high weight gain in infancy and reduces obesity risk in later life by about 20%, presumably partly due to the lower protein supply with human milk than conventional infant formula. In a large randomized clinical trial, we tested the hypothesis that reduced infant formula protein contents lower insulin-releasing amino acid concentrations and thereby decrease circulating insulin and IGF-I levels, resulting in lesser early weight gain and reduced later obesity risk (the 'Early Protein Hypothesis'). The results demonstrate that lowered protein in infant formula induces similar - but not equal - metabolic and endocrine responses and normalizes weight and BMI relative to breastfed controls at the age of 2 years. The results available should lead to enhanced efforts to actively promote, protect and support breastfeeding. For infants that are not breastfed or not fully breastfed, the use of infant formulas with lower protein contents but high protein quality appears preferable. Cows' milk as a drink provides high protein intake and should be avoided in infancy., (Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel.)

Background: Little information is available on infants' age at first introduction of potentially allergenic foods as part of complementary feeding. We aimed to analyze age at the introduction of potentially allergenic foods in healthy term infants relative to recommendations in 5 European countries., Method: Recruitment was conducted from October 2002 to June 2004. A total of 1,678 infants [588 breastfed (BF) and 1,090 formula-fed (FF) infants] were studied. In 1,368 infants, at least one 3-day weighed food diary at the age of 1-9 and 12 completed months was available., Results: Six percent of BF infants and 13% of FF infants consumed some potentially allergenic food already prior to the recommended minimum age of 4 months, and 4% of BF infants and 11% of FF infants had already received gluten. There were significant differences in the timing of the introduction of potentially allergenic foods between the countries at the age of 4-6 months (p < 0.001)., Conclusion: The time of first introduction of potentially allergenic foods in infants differed significantly between countries, and they were introduced much earlier than recommended in some countries. FF infants received potentially allergenic foods earlier than BF infants. Better information and counseling of parents is desirable., (Copyright © 2011 S. Karger AG, Basel.)