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Background: Infant formulas are typically manufactured using skimmed milk, whey proteins, and vegetable oils, which excludes milk fat globule membranes (MFGM). MFGM contains polar lipids, including sphingomyelin (SM)., Objective: The objective of this study was comparison of infant plasma SM and acylcarnitine species between infants who are breastfed or receiving infant formulas with different fat sources., Methods: In this explorative study, we focused on SM and acylcarnitine species concentrations measured in plasma samples from the TIGGA study (ACTRN12608000047392), where infants were randomly assigned to receive either a cow milk-based infant formula (CIF) with vegetable oils only or a goat milk-based infant formula (GIF) with a goat milk fat (including MFGM) and vegetable oil mixture to the age ≥4 mo. Breastfed infants were followed as a reference group. Using tandem mass spectrometry, SM species in the study formulas and SM and acylcarnitine species in plasma samples collected at the age of 4 mo were analyzed., Results: Total SM concentrations (∼42 μmol/L) and patterns of SM species were similar in both formulas. The total plasma SM concentrations were not different between the formula groups but were 15 % (CIF) and 21% (GIF) lower in the formula groups than in the breastfed group. Between the formula groups, differences in SM species were statistically significant but small. Total carnitine and major (acyl) carnitine species were not different between the groups., Conclusions: The higher total SM concentration in breastfed than in formula-fed infants might be related to a higher SM content in human milk, differences in cholesterol metabolism, dietary fatty acid intake, or other factors not yet identified. SM and acylcarnitine species composition in plasma is not closely related to the formula fatty acid composition. This trial was registered at Australian New Zealand Clinical Trials Registry as ACTRN12608000047392., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Our aim was to assess the nutritional safety and suitability of an infant formula manufactured from extensively hydrolyzed protein in comparison to infant formula manufactured from intact protein (both with low and standard protein content). We performed a combined analysis of raw data from two randomized infant feeding studies. An analysis of covariance (ANCOVA) model was used to determine the non-inferiority of daily weight gain (primary outcome; margin -3 g/day), with the intervention group as a fixed factor and geographic region, sex, and baseline weight as covariates (main model). The data of 346 infants exposed to the formula were included in the analysis. The sample size of the per-protocol analysis with 184 infants was too small to achieve sufficient statistical power. The lower limit of the 97.5% confidence interval (-0.807) of the mean group difference in daily weight gain (i.e., 2.22 g/day) was above the -3 g/day margin (full analysis set). Further anthropometric parameters did not differ between the infant formula groups throughout the study. Growth was comparable to breastfed infants. We conclude that the infant formula manufactured from extensively hydrolyzed protein meets infant requirements for adequate growth and does not raise any safety concerns., Competing Interests: A.K. and B.K. declare no conflicts of interest. M.F. is employed by HiPP GmbH & Co. Vertrieb KG, which provided the product and financially sponsored the two studies. M.F. was involved in the design of the combined analysis, the interpretation of the data, and the writing of the manuscript.

Infant formula is the only acceptable substitute for breastmilk from 0 to 6 months old when human milk cannot be provided in sufficient amounts. Manufacturers have developed options that intend to meet the changing needs of the child aged from six to twelve months (follow-on formulae) and after the age of one year (young child formulae). The international code for marketing breast milk substitute stipulates standards for marketing practices of these products. In Latin America there are local variations of marketing practices. Novel marketing strategies such as advertising through social media and influencers pose new threats for breastfeeding success in Latin America. This review aims to examine variations in local regulations for marketing of infant formulae and to analyze the emerging phenomenon of influencer advertising. We reviewed the local norms for Latin American countries and examined differences and possible gaps. Emerging evidence of influencer marketing was explored. The results indicate that national regulations differ among Latin American countries, particularly with respect to product labelling and the requirement to use a local native language, highlighting the cost of the product, and different regulations prohibiting certain messages and illustrations. Regarding new marketing strategies, there is limited evidence on advertising infant formula through social media influencers, where different categories of marketing strategies can be described. More transparent reporting of social marketing by formula providers and more independent research on novel marketing strategies are needed.

Purpose: The objective of this secondary analysis is to describe the types of commercial complementary foods (CCF) consumed by infants and young children enrolled in the European Childhood Obesity Project (CHOP), to describe the contribution of CCF to dietary energy intakes and to determine factors associated with CCF use over the first 2 years of life., Methods: The CHOP trial is a multicenter intervention trial in Germany, Belgium, Italy, Poland and Spain that tested the effect of varying levels of protein in infant formula on the risk for childhood obesity. Infants were recruited from October 2002 to June 2004. Dietary data on CCF use for this secondary analysis were taken from weighted, 3-day dietary records from 1088 infants at 9 time points over the first 2 years of life., Results: Reported energy intakes from CCF during infancy (4-9 months) was significantly higher (p ≤ 0.002) amongst formula-fed children compared to breastfed children. Sweetened CCF intakes were significantly higher (p ≤ 0.009) amongst formula-fed infants. Female infants were fed significantly less CCF and infant age was strongly associated with daily CCF intakes, peaking at 9 months of age. Infants from families with middle- and high-level of education were fed significantly less quantities of CCF compared to infants with parents with lower education. Sweetened CCF were very common in Spain, Italy and Poland, with over 95% of infants and children fed CCF at 9 and 12 months of age consuming at least one sweetened CCF. At 24 months of age, 68% of the CHOP cohort were still fed CCF., Conclusions: CCF comprised a substantial part of the diets of this cohort of European infants and young children. The proportion of infants being fed sweetened CCF is concerning. More studies on the quality of commercial complementary foods in Europe are warranted, including market surveys on the saturation of the Western European market with sweetened CCF products.

Objectives: A high dairy protein intake in infancy, maternal pre-pregnancy BMI, and delivery mode are documented early programming factors that modulate the later risk of obesity and other health outcomes, but the mechanisms of action are not understood., Methods: The Childhood Obesity Project is a European multicenter, double-blind, randomized clinical trial that enrolled healthy infants. Participating infants were either breastfed (BF) or randomized to receive higher (HP) or lower protein (LP) content formula in the first year of life. At the ages 5.5 years (n = 276) and 8 years (n = 232), we determined plasma metabolites by liquid chromatography tandem-mass-spectrometry of which 226 and 185 passed quality control at 5.5 years and 8 years, respectively. We assessed the effects of infant feeding, maternal pre-pregnancy BMI, smoking in pregnancy, delivery mode, parity, birth weight and length, and weight gain (0-24 months) on the metabolome at 5.5 and 8 years., Results: At 5.5 years, plasma alpha-ketoglutarate and the acylcarnitine/BCAA ratios tended to be higher in the HP than in the LP group, but no metabolite reached statistical significance (P bonferroni >0.09). There were no group differences at 8 years. Quantification of the impact of early programming factors revealed that the intervention group explained 0.6% of metabolome variance at both time points. Except for country of residence that explained 16% and 12% at 5.5 years and 8 years, respectively, none of the other factors explained considerably more variance than expected by chance., Conclusions: Plasma metabolome was largely unaffected by feeding choice and other early programming factors and we could not prove the existence of a long term programming effect of the plasma metabolome.

Recently adopted regulatory standards on infant and follow-on formula for the European Union stipulate that from February 2020 onwards, all such products marketed in the European Union must contain 20-50 mg omega-3 DHA (22:6n-3) per 100 kcal, which is equivalent to about 0.5-1% of fatty acids (FAs) and thus higher than typically found in human milk and current infant formula products, without the need to also include ω-6 arachidonic acid (AA; 20:4n-6). This novel concept of infant formula composition has given rise to concern and controversy because there is no accountable evidence on its suitability and safety in healthy infants. Therefore, international experts in the field of infant nutrition were invited to review the state of scientific research on DHA and AA, and to discuss the questions arising from the new European regulatory standards. Based on the available information, we recommend that infant and follow-on formula should provide both DHA and AA. The DHA should equal at least the mean content in human milk globally (0.3% of FAs) but preferably reach 0.5% of FAs. Although optimal AA intake amounts remain to be defined, we strongly recommend that AA should be provided along with DHA. At amounts of DHA in infant formula up to ∼0.64%, AA contents should at least equal the DHA contents. Further well-designed clinical studies should evaluate the optimal intakes of DHA and AA in infants at different ages based on relevant outcomes., (Copyright © The Author(s) 2019.)

Breastfeeding is associated with a reduced later obesity risk, relative to feeding convention infant formula. Breastfeeding induces less weight gain during the first two years of life, which predicts less obesity up to adulthood. We tested the hypothesis that a high infant protein supply promotes weight gain and obesity risk, mediated by increased plasma amino acids and growth factors, insulin and insulin like growth factor 1 (IGF-1). A large multi-centre double blind trial randomized formula-fed infants to conventional bottle milk with a high protein content, or an intervention formula with a reduced protein content more similar to levels provided with human milk. Protein-reduced formula normalized weight, body mass index and body fatness up to 6 years, relative to a breastfed reference group, and reduced the adjusted odds for obesity 2.6-fold. Available data indicate potential underlying mechanisms. We conclude that infant feeding has very marked long-term programming effects on later BMI, obesity and adiposity, with major public health implications. Breastfeeding lowers the risk for later obesity and adiposity. This provides additional motivation for proactively and enthusiastically promoting, protecting and supporting breastfeeding. A high milk protein intake in infancy increases the long-term risk for obesity and adiposity. Infants not or not fully breastfed should receive infant formula delivering protein in amounts more similar to human milk contents, with high protein quality. Other sources of very high infant protein intakes, particular drinking unmodified cows' milk, should be avoided in infancy., (Copyright © 2019. Published by Elsevier Inc.)

In humans, maximum brain development occurs between the third trimester of gestation and 2 years of life. Nutrition during these critical windows of rapid brain development might be essential for later cognitive functioning and behaviour. In the last few years, trends on protein recommendations during infancy and childhood have tended to be lower than that in the past. It remains to be demonstrated that lower protein intakes among healthy infants, a part of being able to reduce obesity risk, is safe in terms of mental performance achievement. Secondary analyses of the EU CHOP, a clinical trial in which infants from five European countries were randomised to be fed a higher or a lower protein content formula during the 1st year of life. Children were assessed at the age of 8 years with a neuropsychological battery of tests that included assessments of memory (visual and verbal), attention (visual, selective, focused and sustained), visual-perceptual integration, processing speed, visual-motor coordination, verbal fluency and comprehension, impulsivity/inhibition, flexibility/shifting, working memory, reasoning, visual-spatial skills and decision making. Internalising, externalising and total behaviour problems were assessed using the Child Behaviour Checklist 4-18. Adjusted analyses considering factors that could influence neurodevelopment, such as parental education level, maternal smoking, child's gestational age at birth and head circumference, showed no differences between feeding groups in any of the assessed neuropsychological domains and behaviour. In summary, herewith we report on the safety of lower protein content in infant formulae (closer to the content of human milk) according to long-term mental performance.

L-5-methyltetrahydrofolate is the predominant folate form in human milk but is currently not approved as a folate source for infant and follow-on formula. We aimed to assess the suitability of L-5-methyltetrahydrofolate as a folate source for infants. Growth and tolerance in healthy term infants fed formulae containing equimolar doses of L-5-methyltetrahydrofolate (10.4 μg/ 100 ml, n = 120, intervention group) or folic acid (10.0 μg/ 100 ml, n = 120, control group) was assessed in a randomized, double-blind, parallel, controlled trial. A reference group of breastfed infants was followed. Both formulae were well accepted without differences in tolerance or occurrence of adverse events. The most common adverse events were common cold, poor weight gain or growth, rash, eczema, or dry skin and respiratory tract infection. Weight gain (the primary outcome) was equivalent in the two groups (95% CI -2.11; 1.68 g/d). In line with this, there was only a small difference in absolute body weight adjusted for birth weight and sex at visit 4 (95% CI -235; 135 g). Equivalence was also shown for gain in head circumference but not for recumbent length gain and increase in calorie intake. Given the nature of the test, this does not indicate an actual difference, and adjusted means at visit 4 were not significantly different for any of these parameters. Infants receiving formula containing L-5-methyltetrahydrofolate had lower mean plasma levels of unmetabolized folic acid (intervention: 0.73 nmol/L, control: 1.15 nmol/L, p<0.0001) and higher levels of red cell folate (intervention: 907.0 ±192.8 nmol/L, control: 839.4 ±142.4 nmol/L, p = 0.0095). We conclude that L-5-methyltetrahydrofolate is suitable for use in infant and follow-on formula, and there are no indications of untoward effects. Trial registration: This trial was registered at ClinicalTrials.gov (NCT02437721)., Competing Interests: BT and RS are employees of DSM Nutritional Products Ltd., MG, CH, and BT are employees of Hipp GmbH & Co. BT and RS are employed by DSM Nutritional Products Ltd., MG and CH are employed by HiPP GmbH & Co and BRT is employed by the HiPP Study center. We declare our adherence to PLOS ONE policies on sharing data and materials and are open to sharing data for research purposes upon request, under conditions respecting the EU General Data Protection Regulation and the protection of personal rights of study subjects.

Background: Although there is a growing number of early childhood obesity prevention programs, only a few of them are effective in the long run. Even fewer reports exist on lifetime cost-effectiveness of early prevention strategies. This paper aimed to assess the lifetime cost-effectiveness of infant feeding modification aiming at reducing risk of later obesity., Methods: The simulation model consists of two parts: (a) Model I used data from the European Childhood Obesity Project (CHOP) trial (up to 6 years) and the German Interview and Examination Survey for Children (KiGGS) (6-17 years) to evaluate BMI trajectories of infants receiving either lower protein (LP) or higher protein (HP) content formula; and (b) Model II estimated lifetime cost-effectiveness based on Model I BMI trajectories. Compared to HP formula, LP formula feeding would incur lower costs that are attributable to childhood obesity across all decades of life., Results: Our analysis showed that LP formula would be cost-effective in terms of a positive net monetary benefit (discounted 3%) as an obesity prevention strategy. For the 19% of infants fed with formula in Germany, the LP strategy would result in cost savings of € 2.5 billion., Conclusions: Our study is one of the first efforts to provide much-needed cost-effectiveness evidence of infant feeding modification, thereby potentially motivating interventionists to reassess their resource allocation.

The relationships between nutrition, metabolic response, early growth and later body weight have been investigated in human studies. The aim of this follow-up study was to assess the long-term effect of infant feeding on growth and to study whether the infant metabolome at the age of 4 months might predict anthropometry at 4 years of age. The Belgrade-Munich infant milk trial (BeMIM) was a randomized controlled trial in which healthy term infants received either a protein-reduced infant formula (1.89 g protein/100 kcal) containing alpha-lactalbumin enriched whey and long-chain polyunsaturated fatty acids (LC-PUFA), or a standard formula (2.2 g protein/100 kcal) without LC-PUFA, focusing on safety and suitability. Non-randomized breastfed infants were used as a reference group. Of the 259 infants that completed the BeMIM study at the age of 4 months (anthropometry assessment and blood sampling), 187 children participated in a follow-up visit at 4 years of age. Anthropometry including weight, standing height, head circumference, and percent body fat was determined using skinfolds (triceps, subscapular) and bioelectrical impedance analysis. Plasma metabolite concentration, collected in samples at the age of 4 months, was measured using flow-injection tandem mass spectrometry. A linear regression model was applied to estimate the associations between each metabolite and growth with metabolites as an independent variable. At 4 years of age, there were no significant group differences in anthropometry and body composition between formula groups. Six metabolites (Asn, Lys, Met, Phe, Trp, Tyr) measured at 4 months of age were significantly associated with changes in weight-for-age z-score between 1 to 4 months of age and BMI-for-age z-score (Tyr only), after adjustment for feeding group. No correlation was found between measured metabolites and long-term growth (up to 4 years of age). No long-term effects of early growth patterns were shown on anthropometry at 4 years of age. The composition of infant formula influences the metabolic profile and early growth, while long-term programming effects were not observed in this study., Competing Interests: All authors have made substantial contributions to the conception and design of the study, or acquisition of data, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content. Each author has seen and approved the contents of the submitted manuscript. This study was financially supported in part by HiPP & Co. Vertrieb KG who supplied the respective formulae during the main study and provided support in the form of salaries for authors (BK, MF, HD, VG). MF carried out analyses while she was employed at the Dr. von Hauner Children’s Hospital Munich, Div. of Metabolic and Nutritional Medicine. She is now an employee at HiPP GmbH & Co Vertrieb KG. BT is an employee of HiPP & Co. Vertrieb KG and received salaries for data collection. These employments do not alter the adherence to PLOS ONE policies on sharing data and materials. The specific roles of these authors are articulated in the ‘author contributions’ section.

Objective: The objective of this study was to investigate the effect of lower protein (LP) versus higher protein (HP) content in infant formula on body composition from 3 months to 6 years., Methods: In a multicenter, double-blind European trial, healthy infants (N = 1,090) were randomly assigned to different protein content formulas (upper [HP] and lower [LP] limits of the European Union regulations in 2001) during the first year; breastfed infants (N = 588) were recruited for reference values. Weight, height, and triceps and subscapular skinfold (SF) thickness were measured repeatedly (N = 650 at 6 years), and body composition was estimated (Slaughter). The 99th percentile of fat mass index reference data were used to assess excess body fat at 6 years., Results: At 2 and 6 years, the study observed greater sum of SFs (Δ 2 years: 0.5 mm, P = 0.026, Δ 6 years: 0.6 mm, P = 0.045), fat mass index (Δ 2 years: 0.12 kg/m², P = 0.008, Δ 6 years: 0.15 kg/m², P = 0.011), and fat-free mass index (Δ 2 years: 0.17 kg/m², P = 0.003, Δ 6 years: 0.18 kg/m², P = 0.010) in the HP group compared with the LP group. At 6 years, the HP group had a twofold higher risk than the LP group for excess body fat (adjusted odds ratio: 2.13, P = 0.019)., Conclusions: Infant formula with HP levels induced greater fat mass in children from 2 to 6 years. Lowering the protein content of infant formula may result in a healthier body composition in early childhood., (© 2018 The Obesity Society.)

Objective: A high protein content of nonhydrolyzed infant formula exceeding metabolic requirements can induce rapid weight gain and obesity. Hydrolyzed formula with too low protein (LP) content may result in inadequate growth. The aim of this study was to investigate noninferiority of partial and extensively hydrolyzed formulas (pHF, eHF) with lower hydrolyzed protein content than conventionally, regularly used formulas, with or without synbiotics for normal growth of healthy term infants., Methods: In an European multi-center, parallel, prospective, controlled, double-blind trial, 402 formula-fed infants were randomly assigned to four groups: LP-formulas (1.9 g protein/100 kcal) as pHF with or without synbiotics, LP-eHF formula with synbiotics, or regular protein eHF (2.3 g protein/100 kcal). One hundred and one breast-fed infants served as observational reference group. As primary endpoint, noninferiority of daily weight gain during the first 4 months of life was investigated comparing the LP-group to a regular protein eHF group., Results: A comparison of daily weight gain in infants receiving LPpHF (2.15 g/day CI -0.18 to inf.) with infants receiving regular protein eHF showed noninferior weight gain (-3.5 g/day margin; per protocol [PP] population). Noninferiority was also confirmed for the other tested LP formulas. Likewise, analysis of metabolic parameters and plasma amino acid concentrations demonstrated a safe and balanced nutritional composition. Energetic efficiency for growth (weight) was slightly higher in LPeHF and synbiotics compared with LPpHF and synbiotics., Conclusions: All tested hydrolyzed LP formulas allowed normal weight gain without being inferior to regular protein eHF in the first 4 months of life. This trial was registered at clinicaltrials.gov, NCT01143233.

Glutamate (Glu) is the most abundant amino acid (AA) in human milk. Available information on Glu supply and metabolism was reviewed, based on an electronic literature search. In 22 cross-sectional global studies with 4,747 women, free Glu increases with lactation duration and contributes to about 38% of total and 63% of dispensable milk AA. Based on these data, a typical breastfed infant obtains a mean free Glu intake of 35.7 mg/kg body weight (bw; upper end of the normal range 134.6 mg/kg), while precisely collected longitudinal data indicate mean intakes of 40 mg/kg and upper range intakes of 70.2 mg/kg. Mean intakes with cows' milk formula at median concentrations are 0.7 mg/kg (upper range 1.0 mg/kg) and with extensive protein hydrolysate formula 171.7 mg/kg bw (upper range 249.8 mg/kg bw), with no indication of untoward effects. Infants almost entirely utilize dietary Glu in splanchnic organs, with no appreciable effect on plasma Glu concentrations. Estimated free Glu intakes in breastfed infants are up to 4.5-fold higher than the acceptable daily intake (ADI) set by the European Food Safety Authority for the total population including infants, and the respective intakes of infants fed a formula based on an extensive protein hydrolysate are up to 8.3-fold higher. There is no reason to assume that feeding human milk or an extensive protein hydrolysate infant formula would be unsuitable or unsafe for infants. Setting an ADI below the range of the normal intake with a safe diet in generally healthy individuals, that is, below 250 mg/kg per day, seems inappropriate., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background: Growth patterns of breastfed and formula-fed infants may differ, with formula-fed infants growing more rapidly than breastfed infants into childhood and adulthood. Objective: Our objectives were to identify growth patterns and investigate early nutritional programming potential on growth patterns at 6 y and on body composition at 20 y. Design: The West Australian Pregnancy Cohort (Raine) Study and 3 European cohort studies (European Childhood Obesity Trial, Norwegian Human Milk Study, and Prevention of Coeliac Disease) that collaborate in the European Union-funded Early Nutrition project combined, harmonized, and pooled data on full breastfeeding, anthropometry, and body composition. Latent growth mixture modeling was applied to identify growth patterns among the 6708 individual growth trajectories. The association of full breastfeeding for <3 mo compared with ≥3 mo with the identified trajectory classes was assessed by logistic regression. Differences in body composition at 20 y among the identified trajectory classes were tested by analysis of variance. Results: Three body mass index (BMI; in kg/m 2 ) trajectory patterns were identified and labeled as follows-class 1: persistent, accelerating, rapid growth (5%); class 2: early, nonpersistent, rapid growth (40%); and class 3: normative growth (55%). A shorter duration of full breastfeeding for <3 mo was associated with being in rapid-growth class 1 (OR: 2.66; 95% CI: 1.48, 4.79) and class 2 (OR: 1.96; 95% CI: 1.51, 2.55) rather than the normative-growth class 3 after adjustment for covariates. Both rapid-growth classes showed significant associations with body composition at 20 y ( P < 0.0001). Conclusions: Full breastfeeding for <3 mo compared with ≥3 mo may be associated with rapid growth in early childhood and body composition in young adulthood. Rapid-growth patterns in early childhood could be a mediating link between infant feeding and long-term obesity risk., (© 2017 American Society for Nutrition.)

Purpose: Insulin-like growth factor-I (IGF-I) is related to growth and its secretion is modified by protein intake in early infancy. We examined the relationship of dietary protein and circulating amino acids on plasma IGF-I levels and early growth., Methods: Healthy formula-fed infants (n = 213) were randomly assigned to receive either a protein-reduced infant formula with alpha-lactalbumin-enriched whey and free tryptophan and phenylalanine (IF) or an isocaloric standard formula without free amino acids (CF) for the first 120 days of life. A group of breastfed (BF) infants was studied as a non-randomized reference cohort. Biochemical variables were measured shortly after birth (subpopulation) and at an age of 120 days. A path analysis was used to explore the relationship between IGF-I, insulin and amino acids. Results are derived from secondary analyses of a randomized controlled trial., Results: Plasma concentrations of IGF-I at 120 days were significantly higher in IF than in CF infants [58.5 (15.0) vs. 53.7 (9.95) ng/mL; p = 0.020]. BF infants showed lower IGF-I concentrations of 41.6 (10.7) ng/mL. All amino acids but Thr and Cit had a more marked effect on insulin than on IGF-I level. Considering weight, sex and feeding group, Trp explained an equal percentage of variance of IGF-I and insulin (total R 2 12.5 % of IGF-I and 12.3 % of insulin), while branched-chain AA explained an up to twofold higher variance of insulin than IGF-I. Compared to CF, IF explained 18.9 % of the IGF-I level (p = 0.03), while for insulin no direct effect was detectable., Conclusion: Higher IGF-I concentrations and growth velocities in infants receiving protein-reduced IF indicate that the protein concentration of an infant formula alone does not control IGF-I levels and growth. Other components (e.g., selected amino acids) of infant formulae might control directly or indirectly via insulin influence IGF-I.

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.)

Background and Aims: The double-blind randomized European Childhood Obesity Project (CHOP) demonstrated that reduced protein content in infant formula leads to a lower body mass index (BMI) up to six years of age. Here we aimed at assessing pre-peritoneal fat, a marker of visceral fat, in children participating in the CHOP trial., Methods and Results: Healthy term formula-fed infants in five European countries were randomized either to higher (n = 550) or lower (n = 540) protein formulas in the first year of life. Infants who were exclusively breastfed for at least three months (n = 588) were enrolled as an observational (non randomized) group. At age 5 years, subcutaneous fat (SC) and pre-peritoneal fat (PP) were measured by ultrasound in a subgroup of 275 children. The PP fat layer was thicker in the higher compared to the lower protein group (adjusted estimated difference: 0.058 cm, 95%CI 0.002; 0.115; p = 0.043), while SC fat was not different. Girls showed a thicker SC fat layer than boys., Conclusions: Higher protein intake in formula-fed infants appears to enhance pre-peritoneal fat tissue accumulation at the age of 5 years, but not of subcutaneous fat, which may trigger adverse metabolic and health consequences., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Introduction: Arachidonic acid (AA) and docosahexaenoic acid (DHA) are important long-chain polyunsaturated fatty acids for neuronal and cognitive development and are ingredients of infant formulae that are recommended but there is no evidence based minimal supplementation level available. The aim of this analysis was to investigate the effect of supplemented AA and DHA on phospholipid metabolism., Methods: Plasma samples of a randomized, double-blind infant feeding trial were used for the analyses of phospholipid species by flow-injection mass spectrometry. Healthy term infants consumed isoenergetic formulae (intervention formula with equal amounts of AA and DHA-IF, control formula without additional AA and DHA-CF) from the first month of life until the age of 120 days. A group of breast milk (BM) -fed infants was followed as a reference., Results: The plasma profile detected in newborns was different from 4 month old infants, irrespective of study group. Most relevant changes were seen in higher level of LPC16:1, LPC20:4, PC32:1, PC34:1 and PC36:4 and lower level of LPC18:0, LPC18:2, PC32:2, PC36:2 and several ether-linked phosphatidylcholines in newborns. The sum of all AA and DHA species at 4 month old infants in the CF group showed level of 40% (AA) and 51% (DHA) of newborns. The supplemented amount of DHA resulted in phospholipid level comparable to BM infants, but AA phospholipids were lower than in BM infants. Interestingly, relative contribution of DHA was higher in ether-linked phosphatidylcholines in CF fed infants, but IF and BM fed infants showed higher overall ether-linked phosphatidylcholines levels., Conclusion: In conclusion, we have shown that infant plasma phospholipid profile changes remarkably from newborn over time and is dependent on the dietary fatty acid composition. A supplementation of an infant formula with AA and DHA resulted in increased related phospholipid species., Competing Interests: The study was financially supported by HiPP GmbH & Co Vertrieb KG (Pfaffenhofen, Germany). This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Background: Proper infant nutrition promotes healthy growth and development and lowers the risk of disease in later life., Methods: This review is based on pertinent articles retrieved by a selective search, including guidelines, meta-analyses, and systematic reviews., Results: Infants should be exclusively breast-fed until at least the age of 4 months. Infants who are no longer being breast-fed, or no longer exclusively so, should be given commercially available low-protein infant formula containing long-chain polyunsaturated fatty acids. Infants with a family history of allergy should be fed with infant formula based on hydrolyzed protein until complementary feeding begins. Complementary feeding should be initiated no earlier than the beginning of the 5th month and no later than the beginning of the 7th; it should include iron derived from meat, as well as fish once or twice a week. Later initiation of complementary feeding is associated with an increased risk of allergies and is not recommended. Ordinary cow's milk should not be drunk in the first year of life. All infants should be given 2 mg of vitamin K at birth, at 7-10 days, and at 4-6 weeks of age, as well as daily oral supplementation of vitamin D (400-500 IE) and fluoride (0.25 mg)., Conclusion: Physicians should advise families about healthful infant nutrition in order to lay the foundation for lifelong good health through a proper diet.

Unlabelled: Effects of the dietary glycaemic load on postprandial blood glucose and insulin response might be of importance for fat deposition and risk of obesity. We aimed to investigate the metabolic effects, acceptance and tolerance of a follow-on formula containing the low glycaemic and low insulinaemic carbohydrate isomaltulose replacing high glycaemic maltodextrin. Healthy term infants aged 4 to 8 completed months (n = 50) were randomized to receive the intervention follow-on formula (IF, 2.1g isomaltulose (Palatinose™)/100mL) or an isocaloric conventional formula (CF) providing 2.1g maltodextrin/100mL for four weeks. Plasma insulinaemia 60 min after start of feeding (primary outcome) was not statistically different, while glycaemia adjusted for age and time for drinking/volume of meal 60 min after start of feeding was 122(105,140) mg/dL in IF (median, interquartile range) and 111(100,123) in CF (p = 0.01). Urinary c-peptide:creatinine ratio did not differ (IF:81.5(44.7, 96.0) vs. CF:56.8(37.5, 129),p = 0.43). Urinary c-peptide:creatinine ratio was correlated total intake of energy (R = 0.31,p = 0.045), protein (R = 0.42,p = 0.006) and fat (R = 0.40,p = 0.01) but not with carbohydrate intake (R = 0.22,p = 0.16). Both formulae were well accepted without differences in time of crying, flatulence, stool characteristics and the occurrence of adverse events. The expected lower postprandial plasma insulin and blood glucose level due to replacement of high glycaemic maltodextrin by low glycaemic isomaltulose were not observed in the single time-point blood analysis. In infants aged 4 to 8 completed months fed a liquid formula, peak blood glucose might be reached earlier than 60 min after start of feeding. Non-invasive urinary c-peptide measurements may be a suitable marker of nutritional intake during the previous four days in infants., Trial Registration: ClinicalTrials.gov NCT01627015.

Background: Protein intake may influence important health outcomes in later life., Objective: The objective of this study was to investigate current evidence on the effects of infant formulas and follow-on formulas with different protein concentrations on infants' and children's growth, body composition, and later risk of overweight and obesity., Methods: In this systematic review, we searched electronic databases (including MEDLINE, Embase, and the Cochrane Library) up until November 2014 for randomized controlled trials (RCTs). Eligible studies had to include children aged 0-3 y who represented the general population and were fed cow milk-based infant formulas with variations in protein concentration. Control groups received lower-protein cow milk-based formulas (as defined by the authors). The primary outcomes were growth, overweight, obesity, and adiposity. Various time points for outcomes assessment were accepted for inclusion. If possible, a meta-analysis was performed., Results: Twelve RCTs met our inclusion criteria. Different formula protein concentrations did not affect linear growth other than a transient effect on mean length at 3 mo observed in a meta-analysis of 4 studies (mean difference, - 0.27 cm; 95% CI: -0.52, -0.02). Lower mean weight and weight z scores obtained from the infants fed lower-protein formulas were observed only from 6 to 12 mo of age. Data from one large RCT showed that consumption of a lower-protein infant formula may reduce body mass index at 12 mo of age and later (12 mo, 24 mo, and 6y) and the risk of obesity at 6 y. Effects on body composition remained unclear., Conclusions: The current evidence is insufficient for assessing the effects of reducing the protein concentration in infant formulas on long-term outcomes, but, if confirmed, this could be a promising intervention for reducing the risk of overweight and obesity in children. In view of the limited available evidence, more studies replicating effects on long-term health outcomes are needed., (© 2016 American Society for Nutrition.)

Objective: Human milk provides a complex mixture of animal lipids, whereas the fat supply of most modern infant formula is based on vegetable oils. We studied the effects of breast-feeding and of feeding infant formula either without or with dairy goat lipids on the composition of infant plasma glycerophospholipids., Methods: Healthy-term infants were randomized double blind to feeding with infant formula based on whole goats' milk (GIF, approximately 60% milk fat and 40% vegetable oils) or a control cows' milk infant formula based on vegetable oils (VIF) from 2 weeks after birth. A reference group of fully breast-fed infants was also followed. At the age 4 months, blood samples were collected and plasma glycerophospholipids were analyzed with liquid chromatography coupled to triple quadrupole mass spectrometry., Results: The group of breast-fed infants showed significantly higher contents of glycerophospholipid species containing sn-2 palmitic acid [PC(16:0/16:0) and PC(18:0/16:0)] and significantly higher contents of glycerophospholipid species containing long-chain polyunsaturated fatty acids than infants in both formula groups. The GIF group demonstrated significantly higher glycerophospholipid species containing myristic acid [LPC(14:0), PC(14:0/18:1), PC(16:0/14:0)] and palmitoleic acid [LPC(16:1), PC(16:0/16:1), and PC(16:1/18:1)] than the VIF group., Conclusions: We conclude that breast-feeding induces marked differences in infant plasma glycerophospholipid profiles compared with formula feeding, whereas the studied different sources of formula fat resulted in limited effects on plasma glycerophospholipids.

Dietary lipids are key for infants to not only meet their high energy needs but also fulfill numerous metabolic and physiological functions critical to their growth, development, and health. The lipid composition of breast milk varies during lactation and according to the mother's diet, whereas the lipid composition of infant formulae varies according to the blend of different fat sources. This report compares the compositions of lipids in breast milk and infant formulae, and highlights the roles of dietary lipids in term and preterm infants and their potential biological and health effects. The major differences between breast milk and formulae lie in a variety of saturated fatty acids (such as palmitic acid, including its structural position) and unsaturated fatty acids (including arachidonic acid and docosahexaenoic acid), cholesterol, and complex lipids. The functional outcomes of these differences during infancy and for later child and adult life are still largely unknown, and some of them are discussed, but there is consensus that opportunities exist for improvements in the qualitative lipid supply to infants through the mother's diet or infant formulae. Furthermore, research is required in several areas, including the needs of term and preterm infants for long-chain polyunsaturated fatty acids, the sites of action and clinical effects of lipid mediators on immunity and inflammation, the role of lipids on metabolic, neurological, and immunological outcomes, and the mechanisms by which lipids act on short- and long-term health.

Background: Nutrition in childhood has an influence on the cardiovascular function later on in life. European Childhood Obesity Project is a multicenter, randomized clinical intervention trial examining the effect of early protein intake on later health outcomes, particularly adiposity and related disorders. The aim of the study was to examine the effect of nutritional intervention--different protein intake in infancy on carotid intima-media thickness (cIMT) at 5 years. The association of cardiovascular risk factors with cIMT was also assessed., Methods: Healthy term formula-fed infants in five European countries were enrolled either to the higher (HP) or to the lower (LP) protein group. Observational group consisted of breastfed infants. Plasma insulin, glucose, lipid profile, IGF-1, apolipoprotein A1 and B were measured as well as anthropometric parameters of parents and a child, blood pressure and physical activity., Results: No difference in cIMT between HP and LP group was observed. Insulin, HOMA-IR index and total IGF-1 were positively associated with cIMT but after adjustment for confounders only an inverse association between ApoA1 and positive between ApoB/ApoA1 and cIMT were significant., Conclusion: High versus low protein intake in infancy does not influence cIMT at 5 years. cIMT in healthy children at 5 years is associated with their apolipoprotein profile., (© 2015 S. Karger AG, Basel.)

Background: There are no internationally agreed recommendations on compositional requirements of follow-up formula for young children (FUF-YC) aged 1-3 years., Aim: The aim of the study is to propose international compositional recommendations for FUF-YC., Methods: Compositional recommendations for FUF-YC were devised by expert consensus based on a detailed literature review of nutrient intakes and unmet needs in children aged 12-36 months., Results and Conclusions: Problematic nutrients with often inadequate intakes are the vitamins A, D, B12, C and folate, calcium, iron, iodine and zinc. If used, FUF-YC should be fed along with an age-appropriate mixed diet, usually contributing 1-2 cups (200-400 ml) of FUF-YC daily (approximately 15% of total energy intake). Protein from cow's milk-based formula should provide 1.6-2.7 g/100 kcal. Fat content should be 4.4-6.0 g/100 kcal. Carbohydrate should contribute 9-14 g/100 kcal with >50% from lactose. If other sugars are added, they should not exceed 10% of total carbohydrates. Calcium should provide 200 mg/100 kcal. Other micronutrient contents/100 kcal should reach 15% of the World Health Organization/Food and Agriculture Organization recommended nutrient intake values. A guidance upper level that was 3-5 times of the minimum level was established. Countries may adapt compositional requirements, considering recommended nutrient intakes, habitual diets, nutritional status and existence of micronutrient programs to ensure adequacy while preventing excessive intakes., (© 2015 S. Karger AG, Basel.)

Many formulas (FM) for infants are nowadays supplemented with LC-PUFA. Due to the susceptibility of LC-PUFA to peroxidation, a potential risk of oxidative stress must be considered. We analyzed the concentration of unsaturated fatty acids to calculate an estimated vitamin E need and the concentration of vitamin E as an important lipophilic antioxidant in LC-PUFA enriched (FM(+), n = 31) and not enriched (FM(-), n = 29) formulas as well as in breast milk (BM, n = 118). No differences were observed in the ratios of vitamin E content to estimated vitamin E need between FM(+) and FM(-). Ratios were consistently above the minimum value according to European law. FM showed similar or higher ratios than BM, except in a worst-case scenario where BM showed higher ratios than FM(+). Our results indicate adequate vitamin E content relative to unsaturated fatty acid content in present-day commercial formulas. Given that breast milk tends to contain higher ratios of vitamin E content to estimated vitamin E need than LC-PUFA enriched formulas (at least in a worst-case scenario), the potential effects of increasing vitamin E content in LC-PUFA enriched formulas should be explored.

Background & Aims: Protein source, macronutrient composition and content of long chain-polyunsaturated fatty acids (LC-PUFA) of infant formulae may influence infant growth. We aimed to assess the effect of a modified infant formula on growth., Methods: In a randomized, double-blind trial, 213 healthy term infants consumed isoenergetic study formulae (intervention formula - IF, control formula - CF) from the first month of life until the age of 120 days. IF (1.89 g protein/100 kcal) contained α-lactalbumin (ALAB) and LC-PUFA, while CF (2.30 g protein/100 kcal) provided standard whey and no LC-PUFA. Anthropometry and dietary intake were regularly assessed. A venous blood sample was obtained on day 120., Results: Both formulae were well-accepted without significant differences in health related observations. Weight gain was not statistically different between formula groups (IF: 30.2 ± 6.3 vs. CF: 28.3 ± 6.5 g/day, mean ± SD, P = 0.06). Length gain was higher in IF (0.11 ± 0.02 vs. 0.10 ± 0.02 cm/day, P = 0.02). Energy intake from formula was higher in CF at 90 and 120 days (IF: 509 ± 117 and 528 ± 123 vs. CF: 569 ± 152 and 617 ± 169 kcal/day, P < 0.01). Protein intake in CF was significantly higher at each assessment. Growth per energy intake was higher in IF compared to CF for weight (6.45 ± 2.01 vs. 5.67 ± 2.21 g/100 kcal, P = 0.02) and length (0.23 ± 0.08 vs. 0.20 ± 0.08 mm/100 kcal, P = 0.04)., Conclusions: The modified infant formula with reduced protein content with added ALAB and LC-PUFA, meets infant requirements of protein for adequate growth. The increased energetic efficiency of the new infant formula might result from improved protein composition by added ALAB. Apparently minor differences in composition can markedly affect energetic efficiency for growth. The study was registered at ClinicalTrials.gov (NCT01094080)., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Early nutrition is recognized as a target for the effective prevention of childhood obesity. Protein intake was associated with more rapid weight gain during infancy-a known risk factor for later obesity., Objective: We tested whether the reduction of protein in infant formula reduces body mass index (BMI; in kg/m(2)) and the prevalence of obesity at 6 y of age., Design: The Childhood Obesity Project was conducted as a European multicenter, double-blind, randomized clinical trial that enrolled healthy infants born between October 2002 and July 2004. Formula-fed infants (n = 1090) were randomly assigned to receive higher protein (HP)- or lower protein (LP)-content formula (within recommended amounts) in the first year of life; breastfed infants (n = 588) were enrolled as an observational reference group. We measured the weight and height of 448 (41%) formula-fed children at 6 y of age. BMI was the primary outcome., Results: HP children had a significantly higher BMI (by 0.51; 95% CI: 0.13, 0.90; P = 0.009) at 6 y of age. The risk of becoming obese in the HP group was 2.43 (95% CI: 1.12, 5.27; P = 0.024) times that in the LP group. There was a tendency for a higher weight in HP children (0.67 kg; 95% CI: -0.04, 1.39 kg; P = 0.064) but no difference in height between the intervention groups. Anthropometric measurements were similar in the LP and breastfed groups., Conclusions: Infant formula with a lower protein content reduces BMI and obesity risk at school age. Avoidance of infant foods that provide excessive protein intakes could contribute to a reduction in childhood obesity. This trial was registered at clinicaltrials.gov as NCT00338689.

Breast-fed and formula-fed infants differ in terms of nutrient intake, growth, and metabolic and endocrine responses. The energetic efficiency, i.e. the weight or length gain per 100 kcal of energy intake, of breast-fed infants is about 11% higher than the energetic efficiency of formula-fed infants. Only limited data is available on the influence of formula composition on the energetic efficiency of infant formulae. We conducted a review of controlled trials to identify the impact of the macronutrient composition of infant formulae on energetic efficiency. An electronic literature search was conducted in February 2014. Intervention trials that investigated the effect of an infant formula with a modified macronutrient composition and reported the weight, length, and nutritional intake of apparently healthy, term, fully formula-fed infants with a normal weight were included. Thirteen trials met the inclusion criteria. The results showed no effect of the total content of energy, carbohydrate, protein, or fat on energetic efficiency. In contrast, small increasing effects of higher glycemic carbohydrates on energetic efficiency were identified. Improved fat absorption via the use of palmitic acid at the sn-2 ester position of triacylglycerol increased the energetic efficiency by 11%. The quality of formula protein, specifically an increased whey-to-casein ratio, an increased α-lactalbumin content, or a higher tryptophan content increased the energetic efficiency by about 13%. We conclude that fat absorption and protein quality have the potential to modulate energetic efficiency and may contribute to the observed differences in growth and metabolism between breast-fed and formula-fed infants., (© 2014 S. Karger AG, Basel.)

Objective: The aim of the study was to compare plasma carnitine profiles in fortified human milk (HM)-fed preterm infants or formula-fed preterm infants., Methods: Plasma acylcarnitine concentrations were determined in 20 formula-fed and 18 HM-fed preterm infants (birth weights between 1000 and 2200 g) by isotope dilution ESI MS/MS technique on study days 0, 14, and 28., Results: Concentrations of free carnitine (FC) and different acylcarnitines did not change during the 4 weeks of the study in infants fed HM. In contrast, in infants fed formula FC increased markedly (day 0: 29.989 [16.646] μmol/L, median [interquartile range], day 14: 43.972 [8.455], P < 0.05) along with increases of short-chain esters (C2 day 0: 5.300 [3.272], day 14: 6.773 [2.127], P < 0.05; C3 day 0: 0.070 [0.059], day 14: 0.110 [0.069], P < 0.05). In contrast, some medium-chain (C8:1, C12) and long-chain esters (C14, C16) decreased significantly in infant formula by day 14, whereas FC and C2 and C3 esters increased further by day 28 (FC: 47.672 [14.753], C2: 7.430 [4.688], C3: 0.107 [0.047])., Conclusions: The altered carnitine ester profile likely reflects active involvement of the carnitine molecule in the buffering, metabolism, and elimination of nonphysiological acyl moieties.

Background and Objective: The estimation of dietary intake remains a challenge in human nutritional studies. In infants, the use of food diaries (FDs) is a suitable method already validated; however, this method is not exempt from error. In formula-fed infants, dilution of powdered formulas may produce errors. Our aim was to develop and validate standard operating procedures (SOPs) for the assessment of dietary intake in formula-fed infants, attending potential sources of error., Methods: We analysed sources of error in a random subsample of 3-day FDs from 100 infants enrolled in the European Childhood Obesity Project. Calculations to estimate intakes were standardised and included in a software tool (SOPsystem). An evaluation of a simulated FD was performed by 9 trained nutritionists and 23 nutrition students (n=225 and n=575 bottle evaluations, respectively) to compare the results obtained when using or not the SOPsystem. Correct answers (%), coefficients of variation, and the time spent (minutes) to assess the simulated FD were analysed., Results: Overall, 60% of the FDs contained reports of incorrect volumes, and 37% reported incorrect formula dilutions. When the SOPsystem was used, correct answers in the simulated FD were more frequent (P<0.001) and the mean coefficient of variation and the time spent were lower (P<0.005 and P<0.01, respectively)., Conclusions: The development and implementation of SOPs with a software tool that identifies specific sources of error in record-keeping achieved a harmonised and improved process for assessing dietary intakes in formula-fed infants, minimising errors in calculations and reducing the work time invested.

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.)

The follow-up formula (FUF) standard of Codex Alimentarius adopted in 1987 does not correspond to the recently updated Codex infant formula (IF) standard and current scientific knowledge. New Zealand proposed a revision of the FUF Codex standard and asked the non-profit Early Nutrition Academy, in collaboration with the Federation of International Societies for Paediatric Gastroenterology, Hepatology, and Nutrition (FISPGHAN), for a consultation with paediatric nutrition experts to provide scientific guidance. This global expert group strongly supports breastfeeding. FUF are considered dispensable because IF can substitute for breastfeeding throughout infancy, but FUF are widely used and thus the outdated current FUF standard should be revised. Like IF, FUF serve as breast milk substitutes; hence their marketing should respect appropriate standards. The compositional requirements for FUF for infants from 6 months onwards presented here were unanimously agreed upon. For some nutrients, the compositional requirements for FUF differ from those of IF due to differing needs with infant maturation as well as a rising contribution of an increasingly diversified diet with advancing age. FUF should be fed with adequate complementary feeding that is also appropriate for partially breastfed infants. FUF could be fed also after the age of 1 year without safety concerns, but different compositional requirements should be applied for optimal, age-adapted milk-based formulations for young children used only after the age of 1 year. This has not been considered as part of this review and should be the subject of further consideration., (Copyright © 2012 S. Karger AG, Basel.)

Introduction: Higher protein intake during the first year of life is associated with increased weight gain velocity and body mass index (BMI). However, the relationship of protein intake and weight gain velocity with body composition is unclear., Objective: To assess if the increases in weight gain velocity and BMI induced by protein intake early in life are related to an increase in fat or fat-free mass., Materials and Methods: In all, 41 infants randomized at birth to a higher or lower protein content formula (HP=17 and LP=24, respectively) and 25 breastfed infants were included. Anthropometric measures were assessed at baseline, 6, 12 and 24 months, and fat-free mass (FFM) and fat mass (FM) were assessed by isotope dilution at 6 months., Results: Weight gain velocity (g per month) during the first 6 months of life was significantly higher among HP infants (807.8 (±93.8) vs 724.2 (±110.0) (P=0.015)). Weight gain velocity strongly correlated with FM z-score (r=0.564, P<0.001) but showed no association with FFM z-scores. FFM showed no association with BMI. Nevertheless, FM strongly correlated with BMI at 6, 12 and 24 months (r=0.475, P<0.001; r=0.332, P=0.007 and r=0.247, P=0.051, respectively). FFM and FM z-scores did not differ significantly between HP and LP infants (0.32±1.75 vs -0.31±1.17 and 0.54±2.81 vs -0.02±1.65, respectively)., Conclusion: Our findings support the hypothesis that higher protein intakes early in life are associated with faster weight gain and in turn to higher adiposity. This mechanism could be a determinant factor for later obesity risk.

Background: Early introduction of solid food has been suspected to induce excessive infant energy intake and weight gain., Objective: The objective of this study was to test whether introduction of solid foods influences energy intake or growth., Design: Healthy, formula-fed infants who were recruited in 5 European countries were eligible for study participation. Anthropometric measurements were taken at recruitment and at 3, 6, 12, and 24 mo. Time of introduction of solid foods and energy intake were determined by questionnaires and 3-d weighed food records at monthly intervals. Age at introduction of solid food was categorized into 4 groups: ≤ 13 wk, 14-17 wk, 18-21 wk, and ≥ 22 wk., Results: Of 1090 recruited infants, 830 (76%) had data available for age at first introduction of solid food, and 671 (61%) completed the study until 24 mo of age. The median age at introduction of solid food was 19 wk. The time of introduction of solid foods was associated with country, sex, birth weight, parental education and marital status, and maternal smoking. Energy intake was higher in the first 8 mo of life in children with solid-food intake. Solid-food introduction did not predict anthropometric measures at 24 mo. Growth trajectories differed significantly: children with solid-food introduction in the first 12 wk experienced early catch-up growth, whereas those introduced to solid food at >22 wk of age grew more slowly and stayed on lower trajectories., Conclusions: Solid foods do not simply replace infant formula but increase energy intake. Time of introduction of solid food has little influence on infant growth. This trial was registered at clinicaltrials.gov as NCT00338689.

Background: The reported effect sizes of early nutrition programming on long-term health outcomes are often small, and it has been questioned whether early interventions would be worthwhile in enhancing public health., Objective: We explored the possible health economic consequences of early nutrition programming by performing a model calculation, based on the only published study currently available for analysis, to evaluate the effects of supplementing infant formula with long-chain polyunsaturated fatty acids (LC-PUFAs) on lowering blood pressure and lowering the risk of hypertension-related diseases in later life., Design: The costs and health effects of LC-PUFA-enriched and standard infant formulas were compared by using a Markov model, including all relevant direct and indirect costs based on German statistics. We assessed the effect size of blood pressure reduction from LC-PUFA-supplemented formula, the long-term persistence of the effect, and the effect of lowered blood pressure on hypertension-related morbidity., Results: The cost-effectiveness analysis showed an increased life expectancy of 1.2 quality-adjusted life-years and an incremental cost-effectiveness ratio of -630 Euros (discounted to present value) for the LC-PUFA formula in comparison with standard formula. LC-PUFA nutrition was the superior strategy even when the blood pressure-lowering effect was reduced to the lower 95% CI., Conclusions: Breastfeeding is the recommended feeding practice, but infants who are not breastfed should receive an appropriate infant formula. Following this model calculation, LC-PUFA supplementation of infant formula represents an economically worthwhile prevention strategy, based on the costs derived from hypertension-linked diseases in later life. However, because our analysis was based on a single randomized controlled trial, further studies are required to verify the validity of this thesis.

Background & Aims: Canola oil is a variety of rapeseed oil low in erucic acid (<2%). For many years, canola oil has been widely used as an ingredient in infant formula in Europe, but not in North America due to safety concerns. A number of studies have used variable canola content of infant formulas to investigate the effects of linoleic acid: α-linolenic acid ratio on visual function of infants. However, little published data is available to compare the safety of canola versus non-canola containing infant formula. The aim of this study is to investigate whether infant formulas containing canola oil support normal growth in infants as assessed by weight and length gain., Methods: Re-analyses of data on infant weight and length gain from a prospective randomized double-blind trial in full-term infants in the German Infant Nutritional Intervention study (GINI). This analysis compared growth in infants receiving infant formulas with or without canola oil from week 4 to month 7. Absolute weight and length, weight and length gain in gram or cm per day and standardized weight and length measurements were analyzed by analyses of variance and a longitudinal random effects model. Standardization was conducted according to the new WHO 2006 age- and sex-specific child growth standards., Results: Absolute and standardized weight and length measures did not differ between the formula groups with or without canola oil. This was true for both, analyses within each of the three anthropometric measurement periods (4-6 weeks, 3-4 months, 6-7 months) and for the longitudinal analyses over the whole period from 4 weeks to 7 months of life. Power analyses confirmed that sample size was sufficient to detect a difference of 3 g per day between 14 and 120 days between the two formula groups., Conclusions: Infant formula containing canola oil supports normal infant growth as assessed by weight and length gain., (Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Protein intake has been directly associated with kidney growth and function in animal and human observational studies. Protein supply can vary widely during the first months of life, thus promoting different kidney growth patterns and possibly affecting kidney and cardiovascular health in the long term. To explore this further, we examined 601 healthy 6-month-old formula-fed infants who had been randomly assigned within the first 8 weeks of life to a 1-year program of formula with low-protein (LP) or high-protein (HP) contents and compared them with 204 breastfed (BF) infants. At 6 months, infants receiving the HP formula had significantly higher kidney volume (determined by ultrasonography) and ratios of kidney volume to body length and kidney volume to body surface area than did infants receiving the LP formula. BF infants did not differ from those receiving the LP formula in any of these parameters. Infants receiving the HP formula had significantly higher serum urea and urea to creatinine ratios than did LP formula and BF infants. Hence, in this European multicenter clinical trial, we found that a higher protein content of the infant formula increases kidney size at 6 months of life, whereas a lower protein supply achieves kidney size indistinguishable from that of healthy BF infants. The potential long-term effects of a higher early protein intake on long-term kidney function needs to be determined.

Objectives: The aim of this study was to describe developed methods for repeated longitudinal assessment of feeding habits and nutrient intakes of children in a multicenter trial in different European countries and to assess feasibility., Patients and Methods: Nutrient intake and dietary habits of formula-fed and breast-fed infants were assessed in 5 European countries (Belgium, Germany, Italy, Poland, and Spain). Prospective age-adapted 3-day weighed food records were used from birth to 2 years of age (1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 18, and 24 months). Standard operating procedures were developed to check each day's food record for quality. Dietitians were trained by using standardized food records. Data entry and nutrient analyses were performed with a dedicated software developed for this project., Results: Of 1368 study participants, at least one 3-day food record was available; of 25,367 1-day food records, data on quality could be evaluated. Overall, between 81% and 97% (depending on the country) of the food records had been completed with high accuracy. The implementation of solid foods and regular family foods decreased the recording quality significantly during the 2-year time course (P < 0.001). The standardized training shows coefficients of variation up to a maximum of about 41%, indicating differences in data entry., Conclusions: The experiences gathered indicate that collecting dietary and behavioral data in a large number of infants from different cultures is a challenging but feasible task in which permanent supervision and training is vital. However, we conclude that the established methodology is suitable to obtain valuable results on current infant nutrition practice in Europe.

Background: Intake of energy providing liquids (EPL) other than breast milk or formula to infants is discouraged because it may displace milk intake. Data on actual practice is lacking., Aim: To describe the current practice of EPL supply to infants in five European countries., Method: Breastfed (BF) infants and infants fed using two formulae (FF) with different protein content were recruited from October 2002 to June 2004. Three-day weighed food protocols of 1368 infants were obtained monthly at the ages of 1 to 9 and again at 12 completed months., Results: At the age of 4 months, 13% of BF and 43% of FF infants received EPL. FF infants started EPL earlier (median 17 weeks) than BF infants (median 30 weeks). EPL intake was associated with a lower intake of formula milk and solids (kcal/d) in the first year of life. Multiple regression analysis showed significant differences in EPL introduction between the individual countries., Conclusion: In contrast to recommendations, EPL is frequently given during the first months of life to breastfed and particularly to formula fed infants. Infants given EPL showed lower intakes of infant formula and solids. Caregivers should receive better counselling on appropriate infant feeding., (Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Metabolic factors acting during limited and sensitive time periods of pre- and postnatal development can induce lasting effects on health and disease risk in later life up to old age, including later obesity risk, which is referred to as early metabolic programming of long-term health. Three meta-analyses of observational studies found that obesity risk at school age was reduced with early breastfeeding compared to formula feeding. We assumed that breastfeeding protects against later obesity by reducing the occurrence of high weight gain in infancy and that one causative factor is the lower protein content of human milk compared to usual infant formulas (the "early protein hypothesis"). We are testing this hypothesis in the European Childhood Obesity Project, a double-blind, randomized clinical trial enrolling 1,678 infants in five countries (Belgium, Germany, Italy, Poland, Spain). We have randomized healthy infants born at term to receive for the first year infant formula and follow-on formula with higher or lower protein contents, respectively. The follow-up data obtained at age 2 years indicates that feeding formula with reduced protein content normalizes early growth relative to a breastfed reference group and the current WHO growth standard, which may furnish a significant long-term protection against later obesity. We conclude that infant feeding practice has a high potential for long-term health effects. The results obtained should stimulate the review of recommendations and policies for infant formula composition.

Background & Aims: There is some evidence that the type of infant formula received in early infancy has an influence on later food preferences. How long potential effects of taste programming persist is however not clear. Therefore, the aim of present study was to investigate whether feeding with different kinds of infant formula is associated with the acceptance of infant formula at 10 years of age., Methods: Preference testing was conducted in 833 10-year old children being part of the interventional subgroup of the German Infant Nutritional Intervention Program Plus Study (GINIplus). If they were not exclusively breastfed, these children have been fed with either one of three hydrolysed formulas or a cow's milk formula during the first four months of life., Results: Feeding with any kind of hydrolysed formula in infancy was positively associated with a higher acceptance of extensively hydrolysed casein formula (aOR: 1.88; 95% CI 1.08, 3.29) after adjusting for sex and study centre., Conclusions: Although this study did not show consistent associations and thus leaves some questions unanswered, it might stimulate further research on the potential programming effect of early infant feeding., (Copyright 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objectives: To find out whether supplementation of formula milk by long-chain polyunsaturated fatty acids (LCPUFA) affects neurodevelopment at 18 months of age in term or preterm infants by an individual patient data (IPD) meta-analysis., Materials and Methods: Data of 870 children from 4 large randomised clinical trials for formula milk with and without LCPUFAs allowed for assessing the effect of LCPUFA with adjustment for potential confounders and extensive subgroup analysis on prematurity, LCPUFA source, and dosage. Any additional clinical trials examining the effect of LCPUFA supplementation on Bayley Scales of Infant Development at 18 months were regarded as relevant. Two relevant studies were identified by MEDLINE, but were not available to us. An IPD meta-analysis was performed with subgroup analyses by preterm delivery, very low birth weight (<1500 g), trials with higher amounts of docosahexaenoic acid (DHA) and arachidonic acid (AA), and specific sources of LCPUFA. The sample size of 870 children was sufficient to detect clinically relevant differences in Bayley Scales even in subgroups., Results: There were no significant differences in mental or psychomotor developmental indexes between LCPUFA-supplemented and control groups for all children or in subgroups. This was confirmed with adjustment for the possible confounders: sex, gestational age, birth weight, maternal age, and maternal smoking. The adjusted mean differences in mental developmental index and psychomotor developmental index for all of the children were -0.8 (95% confidence interval -2.8 to 1.2) and -1.0 (-2.7 to 0.7), respectively., Conclusions: These data based on considerable sample size provide substantial evidence that LCPUFA supplementation of infant formula does not have a clinically meaningful effect on the neurodevelopment as assessed by Bayley scores at 18 months. Inclusion of all relevant data should not have led to differing conclusions except, possibly, for very-low-birth-weight infants.