Low-Protein Infant Formula and Obesity Risk.

Infant formulas have been designed to mimic human milk for infants who cannot be breastfed. The overall goal is to establish similar functional outcomes to assure optimal growth, development, maturation of the immune system, and programming of the metabolic system. However, after decades of improving infant formula, growth patterns and body composition development are still different in formula-fed infants compared to breastfed infants, which could contribute to an increased risk of obesity among formula-fed infants. It has been hypothesized that the lower protein concentration of breast milk compared to infant formula influences infants' growth and body composition. Thus, several trials in formula-fed infants with different protein intake levels have been performed to test this hypothesis. In this review, we discuss the current evidence on low-protein infant formula and obesity risk, including future perspectives and implications.

Long-term effects of a modified, low-protein infant formula on growth and body composition: Follow-up of a randomized, double-blind, equivalence trial.

BACKGROUND & AIM: High protein intake in early life is associated with an increased risk of childhood obesity. Feeding a modified lower-protein (mLP) infant formula (1.7 g protein/100 kcal) until the age of 6 months is safe and supports adequate growth. The aim of the present study is to assess longer-term anthropometry with BMI at 1 and 2 years as primary outcome parameter and body composition in children fed mLP formula. METHODS: Healthy term-born infants received mLP or control formula (CTRL) (2.1 g protein/100 kcal) until 6 months of age in a double-blinded RCT. A breast-fed (BF) group served as a reference. Anthropometry data were obtained at 1 and 2 years of age. At the age of 2 years, body composition was measured with air-displacement plethysmography. Groups were compared using linear mixed model analysis. RESULTS: At 1 and 2 years of age, anthropometry, including BMI, and body composition did not differ between the formula groups (n = 74 mLP; n = 69 CTRL). Compared to the BF group (n = 51), both formula-fed groups had higher z scores for weight for age, length for age, waist circumference for age, and mid-upper arm circumference for age at 1 year of age, but not at 2 years of age (except for z score of weight for age in the mLP group). In comparison to the BF group, only the mLP group had higher fat mass, fat-free mass, and fat mass index. However, % body fat did not differ between feeding groups. CONCLUSIONS: In this follow-up study, no significant differences in anthropometry or body composition were observed until 2 years of age between infants fed mLP and CTRL formula, despite the significantly lower protein intake in the mLP group during the intervention period. The observed differences in growth and body composition between the mLP group and the BF reference group makes it necessary to execute new trials evaluating infant formulas with improved protein quality together with further reductions in protein content. CLINICAL TRIAL REGISTRY: This trial was registered in the Dutch Trial Register (Study ID number NTR4829, trial number NL4677). https://www.trialregister.nl/trial/4677.

Early-Life Metabolic and Hormonal Markers in Blood and Growth until Age 2 Years: Results from a Randomized Controlled Trial in Healthy Infants Fed a Modified Low-Protein Infant Formula.

BACKGROUND: High protein intake in early life is associated with an increased risk of childhood obesity. Dietary protein intake may be a key mechanistic modulator through alterations in endocrine and metabolic responses. OBJECTIVE: We aimed to determine the impact of different protein intake of infants on blood metabolic and hormonal markers at the age of four months. We further aimed to investigate the association between these markers and anthropometric parameters and body composition until the age of two years. DESIGN: Term infants received a modified low-protein formula (mLP) (1.7 g protein/100 kcal) or a specifically designed control formula (CTRL) (2.1 g protein/100 kcal) until 6 months of age in a double blinded RCT. The outcomes were compared with a breast-fed (BF) group. Glucose, insulin, leptin, IGF-1, IGF-BP1, -BP2, and -BP3 levels were measured at the age of 4 months. Anthropometric parameters and body composition were assessed until the age of 2 years. Groups were compared using linear regression analysis. RESULTS: No significant differences were observed in any of the blood parameters between the formula groups (n = 53 mLP; n = 44 CTRL) despite a significant difference in protein intake. Insulin and HOMA-IR were higher in both formula groups compared to the BF group (n = 36) (p < 0.001). IGF-BP1 was lower in both formula groups compared to the BF group (p < 0.01). We found a lower IGF-BP2 level in the CTRL group compared to the BF group (p < 0.01) and a higher IGF-BP3 level in the mLP group compared to the BF group (p = 0.03). There were no significant differences in glucose, leptin, and IGF-1 between the three feeding groups. We found specific associations of all early-life metabolic and hormonal blood parameters with long-term growth and body composition except for IGF-1. CONCLUSIONS: Reducing protein intake by 20% did not result in a different metabolic profile in formula-fed infants at 4 months of age. Formula-fed infants had a lower insulin sensitivity compared to breast-fed infants. We found associations between all metabolic and hormonal markers (except for IGF-1) determined at age 4 months and growth and body composition up to two years of age.

Methods to Assess Fat Mass in Infants and Young Children: A Comparative Study Using Skinfold Thickness and Air-Displacement Plethysmography.

BACKGROUND: Traditionally, fat mass is estimated using anthropometric models. Air-displacement plethysmography (ADP) is a relatively new technique for determining fat mass. There is limited information on the agreement between these methods in infants and young children. Therefore we aimed to longitudinally compare fat mass percentage values predicted from skinfold thicknesses (SFTs) and ADP in healthy infants and young children. METHODS: Anthropometry and body composition were determined at the ages of 1, 4, and 6 months and 2 years. We quantified the agreement between the two methods using the Bland-Altman procedure, linear mixed-model analysis, and intra-class correlation coefficients (ICC). RESULTS: During the first 6 months of life, fat mass% predicted with SFT was significantly different from that measured with ADP in healthy, term-born infants (n = 245). ICCs ranged from 0.33 (at 2 years of age) and 0.47 (at 4 months of age). Although the mean difference (bias) between the methods was low, the Bland-Altman plots showed proportional differences at all ages with wide limits of agreement. CONCLUSIONS: There is poor agreement between ADP and SFTs for estimating fat mass in infancy or early childhood. The amount of body fat was found to influence the agreement between the methods.

A modified low-protein infant formula supports adequate growth in healthy, term infants: a randomized, double-blind, equivalence trial.

BACKGROUND: A high protein intake in early life is associated with a risk of obesity later in life. The essential amino acid requirements of formula-fed infants have been reassessed recently, enabling a reduction in total protein content and thus in protein intake. OBJECTIVES: We aimed to assess the safety of an infant formula with a modified amino acid profile and a modified low-protein (mLP) content in healthy term-born infants. Outcomes were compared with a specifically designed control (CTRL) infant formula. METHODS: In this double-blind, randomized controlled equivalence trial, infants received either mLP (1.7 g protein/100 kcal; n = 90) or CTRL formula (2.1 g protein/100 kcal; n = 88) from enrollment (age ≤ 45 d) to 6 mo of age. A breastfed group served as a reference (n = 67). Anthropometry and body composition were determined at baseline, 17 wk (including safety blood parameters), and 6 mo of age. The primary outcome was daily weight gain from enrollment up until the age of 17 wk (at an equivalence margin of ±3.0 g/d). RESULTS: Weight gain from baseline (mean ± SD age: 31 ± 9 d) up to the age of 17 wk was equivalent between the mLP and CTRL formula groups (27.9 and 28.8 g/d, respectively; difference: -0.86 g/d; 90% CI: -2.36, 0.63 g/d). No differences in other growth parameters, body composition, or in adverse events were observed. Urea was significantly lower in the mLP formula group than in the CTRL formula group (-0.74 mmol/L; 95% CI: -0.97, -0.51 mmol/L; P < 0.001). Growth rates, fat mass, fat-free mass, and several essential amino acids were significantly higher in both formula groups than in the breastfed reference group. CONCLUSIONS: Feeding an infant formula with a modified amino acid profile and a lower protein content from an average age of 1 mo until the age of 6 mo is safe and supports an adequate growth, similar to that of infants consuming CTRL formula. This trial was registered at www.trialregister.nl as Trial NL4677.

Body Composition Using Air Displacement Plethysmography in Children With Intestinal Failure Receiving Long-Term Home Parenteral Nutrition.

BACKGROUND: Children with intestinal failure (IF) are at risk of growth failure, but little information about body composition is available. Our aim was to assess body composition using air displacement plethysmography (ADP) and relate it to clinical and growth parameters. METHODS: In this prospective descriptive observational 2-center cohort study, children aged 2-18 years receiving home parenteral nutrition (PN) for ≥6 months underwent ADP measurement. Fat mass index (FMI) and fat-free mass index (FFMI) standard deviation scores (SDSs) were calculated to normalize for small body size. RESULTS: Twenty-one out of 22 children, median age 7.4 years, underwent successful ADP measurement after a median PN duration of 5.5 years. They were significantly lighter (median weight for age SDS -0.71, P = 0.004) and shorter (median height for age SDS -1.55, P < 0.001) than the normal population mean; 52% were growing below target height range. They had low FFMI (median SDS -1.53, P < 0.001) and high FMI (median SDS 0.80, P = 0.002). Weight for height and body mass index (BMI) were significantly associated with FFMI and BMI with FMI, but children with the same weight and height showed different body composition. In 13 patients with 1-year follow-up, growth and body composition did not change significantly. CONCLUSION: Children with IF receiving long-term PN show lower FFM and higher FM than healthy children. Additionally, children with similar routine growth parameters showed different body composition. Further studies should evaluate the effect of a patient-tailored approach including physical activity and nutrition advice based on body composition.

No Association between Glucocorticoid Diurnal Rhythm in Breastmilk and Infant Body Composition at 3 Months.

OBJECTIVE: Glucocorticoids (GCs) in breastmilk have previously been associated with infant body growth and body composition. However, the diurnal rhythm of breastmilk GCs was not taken into account, and we therefore aimed to assess the associations between breastmilk GC rhythmicity at 1 month and growth and body composition at 3 months in infants. METHODS: At 1 month postpartum, breastmilk GCs were collected over a 24-h period and analyzed by LC-MS/MS. Body composition was measured using air-displacement plethysmography at 3 months. Length and weight were collected at 1, 2, and 3 months. RESULTS: In total, 42 healthy mother-infant pairs were included. No associations were found between breastmilk GC rhythmicity (area-under-the-curve increase and ground, maximum, and delta) and infant growth trajectories or body composition (fat and fat free mass index, fat%) at 3 months. CONCLUSIONS: This study did not find an association between breastmilk GC rhythmicity at 1 month and infant's growth or body composition at 3 months. Therefore, this study suggests that previous observations linking breastmilk cortisol to changes in infant weight might be flawed by the lack of serial cortisol measurements and detailed information on body composition.

The Association between Breastmilk Glucocorticoid Concentrations and Macronutrient Contents Throughout the Day.

BACKGROUND: Glucocorticoids (GCs) in breastmilk follow the maternal hypothalamus⁻pituitary⁻adrenal axis activity and may affect the offspring's growth and neurodevelopment. There is some evidence suggesting that macronutrients in breastmilk also fluctuate throughout the day. We aimed to research whether GCs and macronutrients are correlated in multiple breastmilk samples obtained over a 24-h period. METHODS: A total of 10 mothers provided 45 breastmilk samples collected over a 24-h period. Cortisol and cortisone levels were determined by LC⁻MS/MS, and macronutrients were measured with mid-infrared spectroscopy. Correlations between breastmilk GCs and macronutrients were assessed with Pearson correlations and linear mixed models. RESULTS: No associations were found between breastmilk GCs and macronutrients (cortisol: ß-0.1 (95% confidence interval: -1.0 to 0.7), -4.9 (-12.9 to 3.1) for fat, protein, and carbohydrates, respectively; and -0.3 (-5.6 to 5.0) and cortisone: 0.0 (-2.5 to 2.5), -17.4 (-39.8 to 5.0), and -2.7 (-17.7 to 12.3)) for fat, protein, and carbohydrates, respectively. Adjusting for the time of collection to account for GC rhythmicity did not change the results. CONCLUSION: We found no associations between GCs and macronutrients in human breastmilk. The excretion of GCs in breastmilk and the effects of breastmilk GCs on offspring are, therefore, likely independent of the excretion and effects of the macronutrients.

Optimal nutrition in lactating women and its effect on later health of offspring: A systematic review of current evidence and recommendations (EarlyNutrition project).

BACKGROUND: EarlyNutrition ( www.project-earlynutrition.eu ) is an international research consortium investigating the effects of early nutrition on metabolic programming. OBJECTIVE: To summarize current evidence and standards, recommendations, guidelines, and regulations on nutrition or supplements in lactating women with emphasis placed on long-term health effects in offspring, including cardiovascular disease, hypertension, overweight/obesity, metabolic syndrome, diabetes, or glucose intolerance. METHODS: Medline, Embase, selected databases and websites were searched for documents published between 2010 and 2015. RESULTS: Thirteen documents met the inclusion criteria. Effects of maternal long-chain polyunsaturated fatty acid (LC-PUFA) supplementation on overweight/obesity or hypertension in offspring were assessed in 10 studies. One study described the effect of maternal vitamin D supplementation on overweight/obesity, and the remaining 2 studies assessed the effects of maternal probiotic/synbiotic supplementation during lactation on overweight/obesity or metabolic syndrome in their infants. Forty-one documents contained dietary recommendations on various macro- and micronutrients for lactating women, but without consideration of our long-term health outcomes in infants. CONCLUSION: Literature on nutrition of lactating women and its effect on their infants' later health with respect to metabolic programming outcomes appeared to be scarce, and focused mostly on supplementation of LC-PUFA's. No recent guidelines or recommendations were available, highlighting the significant research gaps regarding this topic.

Nutrition of infants and young children (one to three years) and its effect on later health: A systematic review of current recommendations (EarlyNutrition project).

BACKGROUND: EarlyNutrition ( www.project-earlynutrition.eu ) is an international research project investigating the effects of early nutrition on metabolic programming. OBJECTIVE: To summarize, by performing a systematic review, current standards, recommendations, guidelines, and regulations (hereafter, referred to as documents) on the nutrition of children up to three years of age. Special emphasis was placed on long-term effects of early nutrition, such as the risk of cardiovascular disease, hypertension, overweight, obesity, metabolic syndrome, diabetes, or glucose intolerance. METHODS: MEDLINE, selected databases, and websites were searched for documents published between 2008 and January 2013. RESULTS: Forty two documents met the inclusion criteria. The strongest and most consistent evidence for a protective, long-term effect was documented for breastfeeding. Also, limiting the intake of sodium and rapidly absorbed carbohydrates, use of a specific meal pattern, reducing the consumption of saturated fatty acids by replacing them with polyunsaturated fatty acids, and lowering the intake of trans fatty acids, seems beneficial. Many documents did not evaluate long-term outcomes of interest to us, or reported insufficient or imprecise data. Inconsistency in recommendations for some outcomes and research gaps were identified. CONCLUSIONS: Our findings may serve as a helpful tool in planning further research, preventive actions against important diet-related diseases, and guidelines improvement.

Nutritional interventions or exposures in infants and children aged up to 3 years and their effects on subsequent risk of overweight, obesity and body fat: a systematic review of systematic reviews.

This study, performed as part of the international EarlyNutrition research project (http://www.project-earlynutrition.eu), provides a systematic review of systematic reviews on the effects of nutritional interventions or exposures in children (up to 3 years of age) on the subsequent risk of obesity, overweight and adiposity. Electronic databases (including MEDLINE, Embase and Cochrane Library) were searched up until September 2015. Forty systematic reviews were included. A consistent association of breastfeeding with a modest reduction in the risk of later overweight and obesity in childhood and adulthood was found (the odds decreased by 13% based on high-quality studies), but residual confounding cannot be excluded. Lowering the protein content of infant formula is a promising intervention to reduce the risk of later overweight and obesity in children. There is no consistent evidence of an association of the age of introducing complementary foods, sugar-sweetened beverage or energy intake in early childhood with later overweight/obesity, but there are some indications of an association of protein intake during the complementary feeding period with later overweight/obesity. There was inadequate evidence to determine the effects of other nutritional interventions or exposures, including modifications of infant formula composition, fat intake or consumption of different food groups.

Effect of Donor Milk on Severe Infections and Mortality in Very Low-Birth-Weight Infants: The Early Nutrition Study Randomized Clinical Trial.

IMPORTANCE: Infections and necrotizing enterocolitis, major causes of mortality and morbidity in preterm infants, are reduced in infants fed their own mother's milk when compared with formula. When own mother's milk is not available, human donor milk is considered a good alternative, albeit an expensive one. However, most infants at modern neonatal intensive care units are predominantly fed with own mother's milk. The benefits of add-on donor milk over formula are not clear. OBJECTIVE: To determine whether providing donor milk instead of formula as supplemental feeding whenever own mother's milk is insufficiently available during the first 10 days of life reduces the incidence of serious infection, necrotizing enterocolitis, and mortality. DESIGN, SETTINGS, AND PARTICIPANTS: The Early Nutrition Study was a multicenter, double-blind randomized clinical trial in very low-birth-weight infants (birth weight <1500 g) admitted to 1 of 6 neonatal intensive care units in the Netherlands from March 30, 2012, through August 17, 2014. Intent-to-treat analysis was performed. INTERVENTIONS: Infants received pasteurized donor milk or preterm formula during the first 10 days of life if own mother's milk was not (sufficiently) available. MAIN OUTCOMES AND MEASURES: The primary end point was cumulative occurrence of serious infection (sepsis or meningitis), necrotizing enterocolitis, or mortality during the first 60 days of life. RESULTS: A total of 930 infants were screened for inclusion; 557 were excluded, resulting in 373 infants (183 receiving donor milk and 190 receiving formula) who were evaluated by intent-to-treat analysis (median birth weight, 1066 g; mean gestational age, 28.4 weeks). Own mother's milk comprised 89.1% and 84.5% of total mean intake during the intervention period for the donor milk and formula groups, respectively. The incidence of the combined outcome was not different (85 [44.7%] [formula] vs 77 [42.1%] [donor milk]; mean difference, 2.6%; 95% CI, -12.7% to 7.4%). The adjusted hazard ratio was 0.87 (95% CI, 0.63-1.19; P = .37). CONCLUSIONS AND RELEVANCE: In the current study, pasteurized donor milk and preterm formula as supplemental feeding during the first 10 days of life yielded similar short-term outcomes in very low-birth-weight infants regarding safety and efficacy when own mother's milk availability was insufficient. Future studies investigating longer duration of use of human donor milk on short-term and long-term outcomes are necessary. TRIAL REGISTRATION: trialregister.nl Identifier: NTR3225.

Protein Concentration in Milk Formula, Growth, and Later Risk of Obesity: A Systematic Review.

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.

Optimal growth of preterm infants.

The cause of growth restriction in preterm infants is multifactorial, but it has been estimated that about 50% of the variance in early postnatal growth can be attributed to nutrition. Very low birth weight (VLBW) infants who were born small-for-gestational age (SGA) seem to have the highest risk to become growth restricted. Possibly, the intrauterine growth-retarded preterm infant is metabolically different from its appropriately grown counterpart and therefore has different nutritional needs. Neonatal nutrition and the resulting postnatal growth are major determinants in the short- and long-term outcomes of preterm neonates. Although having favorable effects on neurodevelopmental outcome, rapid postnatal weight gain after a period of nutritional restriction is associated with the development of insulin resistance and metabolic syndrome in later life. It seems likely that minimization of postnatal growth failure will decrease the need for catch-up growth and thereby decrease the risk of developing cardiovascular risk factors. Monitoring postnatal growth with current growth charts is complicated. Most growth charts that are currently being used are a reflection of current (nutritional) practices and are not a prescription of how VLBW should grow under optimal conditions. In addition to body weight, other aspects of growth such as lean body mass and length gain should also be taken into account when assessing the quality of postnatal growth. Noninvasive measurements of infant body composition are useful tools in evaluating the success of different nutritional interventions. However, all currently available methods have substantial drawbacks. A relatively new and promising method is air displacement plethysmography. This method still needs to be validated in preterm neonates. In conclusion, neonatal nutrition is a major determinant in the short- and long-term outcomes of preterm neonates. Monitoring postnatal growth is complicated by the lack of prescriptive growth charts and noninvasive measurements to assess the quality of growth.

Intake of own mother's milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life.

BACKGROUND: The incidence of necrotizing enterocolitis (NEC) and possibly also of sepsis is lower in preterm infants fed their own mother's milk (hereafter 'mother's milk') compared with formula-fed infants. It is unclear whether this is caused by the protective properties of breast milk or by the absence of cow's milk. Especially in early life, mother's milk is often unavailable to preterm infants, while minimal enteral nutrition is initiated immediately. OBJECTIVES: To determine whether there is an association between intake of mother's milk during the first days of life and the combined outcome of sepsis, NEC and death over a prolonged period. METHODS: Retrospective study in infants with a birth weight <1,500 g. Intake of mother's milk and formula during the first 10 days of life was recorded. The occurrence of sepsis, NEC and death was registered during the first 60 days. Data were analysed using Cox regression analysis, taking confounders into account. RESULTS: In total, 349 infants were included. Intake of mother's milk during the first 5 days of life was associated with a lower incidence of NEC, sepsis and/or death during the first 60 days of life (hazard ratio (HR) in the category 0.01-50% intake of mother's milk: 0.49, 95% confidence interval (CI) 0.28, 0.87; HR in the category 50.01-100% intake of mother's milk: 0.50, 95% CI 0.31, 0.83, both compared to no mother's milk). During days 6-10, the protective effect was only present if >50% of the total intake was mother's milk (HR = 0.37, 95% CI 0.22, 0.65). CONCLUSION: The type of enteral nutrition during the first 10 days of life is associated with the risk of NEC, sepsis and/or death during the first 60 days of life.