Early Nutrition Must Be Safe and Should Have Positive Impacts on Long-Term Health.

The Special Issue entitled 'The Role of Feeding Practice and Early Nutrition in Infant Growth, Metabolism and Body Composition' examines the long-term outcomes of early nutrition in both preterm and term infants [...].

External validation of a prediction model for estimating fat mass in children and adolescents in 19 countries: individual participant data meta-analysis.

OBJECTIVE: To evaluate the performance of a UK based prediction model for estimating fat-free mass (and indirectly fat mass) in children and adolescents in non-UK settings. DESIGN: Individual participant data meta-analysis. SETTING: 19 countries. PARTICIPANTS: 5693 children and adolescents (49.7% boys) aged 4 to 15 years with complete data on the predictors included in the UK based model (weight, height, age, sex, and ethnicity) and on the independently assessed outcome measure (fat-free mass determined by deuterium dilution assessment). MAIN OUTCOME MEASURES: The outcome of the UK based prediction model was natural log transformed fat-free mass (lnFFM). Predictive performance statistics of R2, calibration slope, calibration-in-the-large, and root mean square error were assessed in each of the 19 countries and then pooled through random effects meta-analysis. Calibration plots were also derived for each country, including flexible calibration curves. RESULTS: The model showed good predictive ability in non-UK populations of children and adolescents, providing R2 values of >75% in all countries and >90% in 11 of the 19 countries, and with good calibration (ie, agreement) of observed and predicted values. Root mean square error values (on fat-free mass scale) were <4 kg in 17 of the 19 settings. Pooled values (95% confidence intervals) of R2, calibration slope, and calibration-in-the-large were 88.7% (85.9% to 91.4%), 0.98 (0.97 to 1.00), and 0.01 (-0.02 to 0.04), respectively. Heterogeneity was evident in the R2 and calibration-in-the-large values across settings, but not in the calibration slope. Model performance did not vary markedly between boys and girls, age, ethnicity, and national income groups. To further improve the accuracy of the predictions, the model equation was recalibrated for the intercept in each setting so that country specific equations are available for future use. CONCLUSION: The UK based prediction model, which is based on readily available measures, provides predictions of childhood fat-free mass, and hence fat mass, in a range of non-UK settings that explain a large proportion of the variability in observed fat-free mass, and exhibit good calibration performance, especially after recalibration of the intercept for each population. The model demonstrates good generalisability in both low-middle income and high income populations of healthy children and adolescents aged 4-15 years.

Effects of Movement Behaviors on Overall Health and Appetite Control: Current Evidence and Perspectives in Children and Adolescents.

PURPOSE OF REVIEW: To present the definitions and recommendations for movement behaviors in children and adolescents, including physical activity (PA), sedentary behaviors (SB), and sleep, and to provide an overview regarding their impact on health and obesity outcomes from childhood to adulthood, as well as interactions with appetite control. RECENT FINDINGS: PA represents a variable proportion of daily energy expenditure and one can be active with high SB or vice versa. Studies have described movements across the whole day on a continuum from sleep to SB to varying intensities of PA. More PA, less SB (e.g., less screen time) and longer sleep are positively associated with indicators of physical health (e.g., lower BMI, adiposity, cardiometabolic risk) and cognitive development (e.g., motor skills, academic achievement). However, less than 10% of children currently meet recommendations for all three movement behaviors. Movement behaviors, adiposity, and related cardiometabolic diseases in childhood track into adolescence and adulthood. Furthermore, low PA/high SB profiles are associated with increased energy intake. Recent studies investigating energy balance regulation showed that desirable movement behavior profiles are associated with better appetite control and improved eating habits. Early identification of behavioral phenotypes and a comprehensive approach addressing all key behaviors that directly affect energy balance will allow for individual strategies to prevent or treat obesity and its comorbidities. Investigating exercise as a potential "corrector" of impaired appetite control offers a promising weight management approach.

Human Milk Fortifiers for Preterm Infants: Do We Offer the Best Amino Acid Mix?

For preterm and small-for-gestational age infants on enteral nutrition, the best solution is to add human milk fortifier (HMF) to human milk (HM) which is provided by the mother or a milk bank. HMF provides a means to add additional protein, energy, and micronutrients, while maintaining HM as the main source of nutrition. Because of their rapid increase of lean body mass, preterm infants have much higher protein requirements than term infants. Recommendations on protein requirements of preterm infants are available, but protein quality - i.e. the amino acid (AA) profile in HMFs has not been systematically assessed. Present guidelines for enteral nutrition recommend protein intakes around 4 g/kg body weight (BW) for preterm infants <1,500 g, an intake that is not achievable with unfortified HM intakes <200 mL/kg BW/day. It is generally assumed that the AA profile of HM is the best reference for the AA profile of HMF. We calculated advisable intakes of AAs for preterm infants between 400-2,500 g which are based on AA increments of the fetus. Corrections for absorption, inevitable losses, oxidation, and variation of AAs in HM were introduced. Our calculations indicate that extremely low birth weight (ELBW <1,000 g) and very low birth weight (VLBW <1,500 g) infants have substantially higher AA requirements than low birth weight (LBW) infants growing from 1,900 to 2,400 g. In ELBW infants, daily intakes of the different indispensable AAs (IAA) with 4 g of (term) HM protein/kg BW range between 59 and 125% of the respective advisable intakes. Intakes of 7 IAAs and 3 conditionally indispensable AAs (CIAA) are below advisable intakes. On the other hand, with 4 g HM protein per kg BW/day, the IAAs isoleucine and leucine and some dispensable AAs are already supplied in abundance. In VLBW infants, daily intakes of the IAA methionine and 3 CIAAs are still below the advisable intakes. In LBW infants (<2,000 g) receiving 3.5 g HM protein per kg BW daily intakes of 1 IAA and 3 CIAAs would be too low. Preterm infants should receive HMFs which provide adequate amounts of AAs which are needed for their rapid growth and development while avoiding excessive intakes. In particular, very high AA requirements of ELBW infants are a challenge. AA composition of present HMFs for preterm infants should be reconsidered: spiking HMF protein with the AAs which are presently undersupplied or providing targeted AA-based HMF are options to further improve the AA profile in fortifiers.

New Ways to Provide a Human Milk Fortifier during Breastfeeding.

Providing a human milk fortifier once the preterm infant has started to suckle at the breast can be challenging for the mother and might shorten duration of the breastfeeding period. Fortification is recommended up to term for the normal-growing infant and up to 3 months in growth-retarded infants. After hospital discharge, some mothers may not want to pump, fortify, and bottle-feed the fortifier-milk mixture any longer. They desire to breastfeed their infants directly from the breast, but unfortunately, fortification often interferes with direct breastfeeding. Cup feeding is the most researched fortification method and appears to be safe but cannot be applied during nursing. Another alternative is the supplemental nursing systems, but only a few low-quality studies investigated the method, which is difficult to handle and requires a lot of nursing experience. The use of a finger feeder to administer a fortifier to preterm infants is a new method that enables mothers to exclusively breastfeed their infants and meet their nutritional needs. Mothers reported easy preparation and handling of the fortifier. More than 67% of the infants accepted the device and fortifier application during nursing very well. However, the development of further methods to augment preterm infant nutrition that does not interfere with breastfeeding is of great interest. Future efforts to enable fortification during breastfeeding must be linked to the development of ready-to-use devices containing liquid human milk fortification mixtures.

Early-Life Nutrition, Growth Trajectories, and Long-Term Outcome.

It is well established that nutrition during the first 1,000 days of life can have a long-term effect on growth, metabolic outcome, and long-term health. We review the long-term anthropometric follow-ups of children with risk of later morbidity: (a) very-low-birth-weight (VLBW) infants who have birth weights <10th percentile of weight and receive fortified breast milk, (b) infants from developing countries who are breastfed according to the present recommendations but have low birth weight and length, and (c) children from developed countries who were enrolled in randomized controlled trials (RCTs) to test if breastfeeding and low-protein formulas can prevent from rapid weight gain and childhood obesity. VLBW infants can be appropriate, small for gestational age (SGA), or intrauterine growth retarded (IUGR). SGA and IUGR (due to placenta insufficiency) infants are born with birth weights <10th percentile of weight for gestational age (GA). We provided fortified breast milk until 52 weeks of GA to 31 SGA and 127 IUGR infants and followed up growth until 24 months. IUGR infants showed lower weight gain between birth and 3 months and had lower weight between 3 and 24 months (p < 0.05; ANCOVA). No significant BMI differences between SGA and IUGR infants were observed. It seems that IUGR infants receiving fortified breast milk need special attention, because without further improvement in breast milk fortification weight gain after discharge from hospital might be too slow. In developing countries, length and weight of breastfed infants during the first 2 years are strongly influenced by the respective anthropometric parameters at birth. Studies in the Gambia and Zimbabwe indicate that only breastfed infants with birth length and weight above the respective WHO 0 z-scores continue with adequate growth and have length and weight above the WHO 0 z-scores at 18 and 24 months. Prevalence of stunting and wasting in the overall Gambia breastfed infant population rapidly increases during the first year, peaks at around 3 years, but decreases thereafter. Long-term growth trajectories indicate later start of puberty and slow pubertal growth, but adult weight and height are not reached before 20-24 years. In adulthood, prevalence of stunting and wasting is much lower than during any period of childhood. Maternal risk factors, such as childhood marriage and poor nutrition before and during pregnancy, need to come into focus to improve birth length and weight and lower high stunting rates. Term breastfed infants from overweight/obese mothers and breastfed infants with rapid weight gain during infancy have increased risk of childhood obesity. Infants who are exclusively breastfed 4-6 months or receive low protein follow-up formulas (high-quality protein) grow slower during the first 2-3 years than infants fed high-protein formulas. During follow-up examinations at 5-6 years, they have lower BMI and obesity prevalence. Body composition measurements (DEXA) at 5-8 years in children who were breastfed and received low- or high-protein formula during infancy indicate that breastfeeding and feeding low-protein formulas are associated with lower gain of fat mass. Longitudinal cohort studies show that high-protein intake during the first 2 years results in higher BMI at 9 years and during adulthood. The studies presented indicate that breastfeeding but also other pre- and postnatal nutritional, epigenetic, and environmental factors influence growth trajectories and long-term health.

Growth of infants consuming whey-predominant term infant formulas with a protein content of 1.8 g/100 kcal: a multicenter pooled analysis of individual participant data.

BACKGROUND: High protein intake during infancy may contribute to obesity later in life in infants who are not exclusively breastfed. Lowering the protein content of infant formula so it is closer to that of mature breast milk may reduce long-term risk of overweight or obesity in formula-fed infants. OBJECTIVE: We assessed the effects of whey-predominant formulas with a protein content of 1.8 g/100 kcal (lower than that in most current formulas and closer to breast milk) on infant growth by comparing against WHO growth standards and breastfed infants. DESIGN: A multicenter pooled analysis was conducted with the use of individual participant data (n = 1882) from 11 randomized controlled trials of healthy term infants. Mixed-effects models that used ANCOVA were generated to estimate weight-for-age z score (WAZ), as well as length-for-age, BMI-for-age, and head circumference-for-age z scores at age 4 mo in infants fed a lower-protein infant formula (LPF) or a lower-protein infant formula with additional active ingredients (probiotics, prebiotics, or both) (LPFA) and breastfed infants. Estimates, including 95% CIs, were compared with a ±0.5 SD of WHO growth standards, a benchmark for clinically significant differences. RESULTS: The 95% CIs for pooled estimates of WAZ were within ±0.5 SD of WHO growth standards for the LPF [0.07 (-0.16, 0.29)] and LPFA [0.22 (0.01, 0.43)] groups. WAZ was higher in the LPF (P < 0.001) and LPFA (P = 0.003) groups than in the breastfed infants, likely because breastfed infants had a relatively low WAZ [-0.23 (-0.51, 0.05)] compared with WHO growth standards. The 95% CIs for all other z scores in the LPF and LPFA groups were within ±0.5 SD of WHO growth standards, except for head circumference, for which the upper limit of the 95% CI slightly exceeded 0.5 SD. No difference was observed in any z scores between the LPF and LPFA groups. CONCLUSION: Whey-predominant infant formula with a lower protein content that more closely resembles that of breast milk supports healthy growth comparable to the WHO growth standards and close to breastfed infants.

Metabolic Programming: Effects of Early Nutrition on Growth, Metabolism and Body Composition.

High protein requirements of premature infants during the first weeks of postnatal life are a well-established fact. Those infants gain fat-free mass and protein rapidly during the first weeks of postnatal growth and require a much higher protein/energy ratio than term infants. Recommended protein intakes are 3.5-4.0 g/kg per day. For term infants, on the other hand, FAO and WHO have recently lowered recommended protein intakes to better reflect our current knowledge about the protein concentration in breast milk during the first 12 months of lactation. Longitudinal randomized clinical trials now confirm that term infants who are fed infant and follow-up formulas with protein concentrations >2.25 g/100 kcal (high protein formulas) during the first year of life grow faster than indicated by the WHO growth standards. Rapid weight gain during infancy is a predictor of childhood and adult obesity. Infants fed high protein quality formulas with protein concentrations of 1.6-2.2 g/100 kcal from 3 to 4 months onwards experience weight gain that is very close to that of breastfed infants. Biomarkers (insulin or IGF-1) of infants receiving low protein formulas differ from those of infants receiving high protein formulas. Six-year-old children who received low protein formulas in the first year of life had a lower risk of childhood obesity (BMI >95th percentile of WHO standards) compared with children who received high protein formulas as infants. BMI at 5 years of age is similar in children who were breastfed or received low protein formulas as infants. It is most important that the new low protein formulas are safe and adequate for all healthy term infants. Based on new protein technologies, the levels of essential and branched-chain amino acids in low protein formulas are now close to those in breast milk. Safety has been confirmed by following anthropometric parameters to 5-6 years of age and comparing these parameters with the WHO growth standards. Body composition measurements indicate similar protein accretion between 3 and 6 months of age in infants fed high or low protein formulas. Longitudinal data on body composition indicate that children who received a low protein formula until age 12 months gain less fat between 6 and 60 months than children who received a high protein formula. Breastfeeding and the use of low/high protein quality formulas in term infants who cannot be breastfed can help support appropriate metabolic programming during this critical period and reduce the risk of later obesity.

Postnatal High Protein Intake Can Contribute to Accelerated Weight Gain of Infants and Increased Obesity Risk.

Worldwide, 38% of women are now overweight (BMI 25-30) or obese (BMI ≥30). There is increasing evidence that maternal obesity can result in unfavorable (epigenetic) pre- and postnatal programming of important genes of the offspring. Infants of overweight mothers show faster weight gain during infancy, which is associated with higher risk of obesity during childhood and adult life. This can have lifelong consequences such as increased risk of noncommunicable diseases. Many studies indicate that infants of obese and nonobese mothers who were fed traditional (high-protein) formulas gain more rapidly weight than breastfed infants. An updated meta-analysis (n = 1,150) indicates that infants from four continents who were fed a whey-based, low-protein (1.8 g/100 kcal) formula with an essential amino-acid profile closer to breast milk grow in accordance with the World Health Organization (WHO) growth standard (0-4 months). A new experimental low-protein (1.61-1.65 g protein/100 kcal) formula for infants between 3 and 12 months of age was recently tested in two randomized clinical trials. One trial in the general US population indicates lower weight between 4 and 12 months of age in infants fed the low-protein formula when compared to infants on the high-protein formula (p = 0.031). Weight gain was not inferior to the WHO growth standards. Longitudinal analysis of odds ratios from 4 to 12 months of age showed a lower incidence of infants with weight >85th percentile in the low-protein group compared with the high-protein group (p = 0.015). In the second trial, which was conducted in Chile and included infants of mothers with BMI >25, infants fed the low-protein formula gained less weight between 4 and 12 months (p = 0.022) and until 24 months (p = 0.031) than the high-protein group. Weight gain was similar to the breastfed reference group. In both trials, biomarkers of protein metabolism (insulin-like growth factor-1 and C-peptide) of the low-protein groups were closer to breastfed infants than the respective biomarkers of the high-protein groups. Health economic analyses indicate that feeding low-protein formulas to nonbreastfed infants would result in cost savings for both the individual and the society. Preventive measures against childhood and adult obesity should include promotion of breastfeeding for 6 months or longer, and use of low-protein formulas in nonbreastfed infants.

Nutritive and Bioactive Proteins in Breastmilk.

Protein ingested with breast milk provides indispensable amino acids which are necessary for new protein synthesis for growth and replacement of losses via urine, feces, and the skin. Protein gain in the body of an infant is highest during the first months when protein concentrations in breast milk are higher than during later stages of lactation. Low-birth-weight infants have higher protein needs than term infants and need protein supplements during feeding with breastmilk. Based on our better understanding of protein evolution in breastmilk during the stages of lactation, new infant formulas with lower protein concentration but better protein quality have been created, successfully tested, and are now available in many countries. Besides providing indispensable amino acids, bioactive protein in breast milk can be broadly classified into 4 major functions, that is, providing protection from microbial insults and immune protection, aiding in digestive functions, gut development, and being carriers for other nutrients. Individual proteins and their proposed bioactivities are summarized in this paper in brief. Indeed, some proteins like lactoferrin and sIgA have been extensively studied for their biological functions, whereas others may require more data in support to further validate their proposed functions.

Adequacy of Infant Formula With Protein Content of 1.6 g/100 kcal for Infants Between 3 and 12 Months.

OBJECTIVES: Infant formulas provide more protein than breast milk. High protein intakes may place infants at risk of later obesity. The present study tested whether a formula with protein content below the regulatory level supports normal growth from age 3 months. METHODS: Randomized double-blind trial enrolled healthy infants less than age 3 months. At 3 months, formula-fed infants were assigned to experimental (EXPL, 1.61 g protein/100 kcal; modified bovine whey proteins with caseinoglycomacropeptide removed) or control (CTRL 2.15 g protein/100 kcal; unmodified bovine milk protein with a whey/casein ratio of 60/40) formula; breast-fed (BF) infants were enrolled in a reference group. Complementary foods were allowed in small amounts from 4 to 6 months and unrestricted after 6 months. RESULTS: Weight gain (g/day) from 3 to 6 months was similar in the EXPL and CTRL groups (EXPL-CTRL -0.84 g/day; 95% confidence interval -2.25 to 0.57) and faster in the EXPL and CTRL groups than in the BF group. Weight analyzed longitudinally from 4 to 12 months was lower in the EXPL group than in the CTRL group (P = 0.031) but higher than in the BF group (P < 0.0001). Longitudinal analysis of odds ratios from 4 to 12 months indicated fewer infants with weight >85th percentile in the EXPL group than in the CTRL group (P = 0.015). Length z scores were lower than, and body mass index z scores were similar to, World Health Organization Standards in all of the groups. Serum biochemical parameters in the EXPL group reflected lower protein intake and were closer to parameters in the BF infants than in the CTRL group. CONCLUSIONS: A formula with 1.61 g of protein/100 kcal supports normal growth of infants after age 3 months. This protein content is adequate if provided from a high-quality source.

Fast growth of infants of overweight mothers: can it be slowed down?

Data from 3 recently completed studies were pooled and analyzed to answer the question whether breastfed infants of overweight/obese mothers show accelerated growth. It was shown that these infants gain weight faster than indicated by the WHO standards and that they grow significantly faster than infants of lean mothers. The question whether fast infant growth can be slowed down by lowering the protein content of formulas was examined. It was shown that formulas with a protein content that is just moderately above that of human milk support normal growth while significantly slowing down fast growth.