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Amino acids form one of the main building blocks for fetal and neonatal growth. Despite improvements in neonatal care, including postnatal nutrition, growth faltering and suboptimal outcome after premature birth are still frequently encountered. Nutrition can partly be held responsible. Over the years, there has been a trend in delivering amino acids earlier from birth on and in larger quantities. Unfortunately, little is known about the specific metabolism of proteins, especially during fetal life or during disease. This review gives an overview of different methods of studying metabolism during early life and what we have come to learn so far. Different examples are given on the complex interplay between the placenta and the fetus. From both ovine and human studies, we know that amino acids are not only used for protein synthesis in the fetus, they are also oxidized to a large extent. Postnatally, we have succeeded in improving the nitrogen balance in preterm infants, but the preconditions need also to be improved before concluding that today's policy is optimal. Only by gaining more knowledge on both fetal and neonatal physiology and disease will we be able to further optimize growth and functional outcome in premature infants., (© 2016 Nestec Ltd., Vevey/S. Karger AG, Basel.)

Objective: Threonine is one of the essential amino acids. Its major fate is incorporation into intestinal mucosal proteins and synthesis of secretory glycoproteins. Therefore, it has an important function in the neonatal gut barrier integrity. The objective was to quantify the threonine requirement in fully enterally fed term neonates by means of the indicator amino acid oxidation (IAAO) method, using L-[1-C]phenylalanine as indicator., Methods: After a 24-hour test diet adaptation, containing randomly assigned amounts of threonine (range 5-182 mg · kg · day), the participating neonates received a primed continuous infusion of [C]bicarbonate and L-[1-C]phenylalanine. At baseline and during the plateau phase of both infusions, breath samples were obtained for CO2. The fractional L-[1-C]phenylalanine oxidation (FCO2) was estimated and plotted against the threonine intakes. Biphasic linear regression crossover analysis was used to calculate the breakpoint of the FCO2, representing the mean threonine requirement. Data are presented as mean ± SD., Results: Thirty-two term neonates (gestational age 39 ± 1 weeks, birth weight 3.3 ± 0.3 kg, mean postnatal age 10 ± 4 days) were studied. The mean threonine requirement was estimated to be 68 mg · kg · day with an upper and lower 95% confidence interval of 104 and 32 mg · kg · day, respectively (r = 0.37)., Conclusions: The determined threonine requirement is extremely close to the existing requirement recommendations (∼90% of the present World Health Organization requirement guidelines). Infant formula preparations presently on the market, however, contain up to twice as much threonine as recommended. The threonine intake in formula-fed infants may therefore be reduced considerably.

Background: Phenylalanine, which is an essential aromatic amino acid, is either used for protein synthesis or irreversibly hydroxylated to tyrosine. The provision of optimal amounts of dietary phenylalanine is not only important for growth and development but might also influence catecholamine synthesis and release rates. The current recommended aromatic amino acid requirement for infants aged 0-6 mo is based on the amino acid content of human milk., Objective: We quantified the requirements for phenylalanine in the presence of excess tyrosine (166 or 177 mg/kg per day for term and preterm infants, respectively) for term and preterm neonates by using the indicator amino acid oxidation method with l-[1-(13)C]lysine 2HCl as an indicator. Hence, we determined the minimum obligatory phenylalanine requirement., Design: Fully enterally fed term and preterm infants received randomly graded amounts of phenylalanine (5-177 mg/kg per day) as part of an elemental formula. Data are expressed as means ± SDs., Results: Twenty term (birth weight: 3.19 ± 0.34 kg; gestational age: 38.9 ± 1 wk) and 16 preterm (birth weight: 1.75 ± 0.17 kg; gestational age: 32.5 ± 0.6 wk) Asian infants participated at a postnatal age of 17 ± 8 d. In total, 44 studies were performed. The minimum obligatory phenylalanine requirement was 58 mg/kg per day (95% CI: 38-78 mg/kg per day) and 80 mg/kg per day (95% CI: 40-119 mg/kg per day) for term and preterm infants, respectively., Conclusion: The determined mean phenylalanine-requirement estimates are lower than the contents of term and preterm formulas currently on the market. This trial was registered at www.trialregister.nl as NTR1610., (© 2015 American Society for Nutrition.)

Objectives: Tryptophan not only is an amino acid essential to protein synthesis but also serves as a precursor in 2 important metabolic pathways: the serotonin and the kynurenine pathways. Tryptophan is related to sleeping patterns. The objective of the present study was to determine the tryptophan requirement of term infants using the indicator amino acid oxidation (IAAO) method with L-[1-C]phenylalanine as the indicator., Methods: Enterally fed infants were randomly assigned to tryptophan intakes ranging from 0.5 to 73 mg · kg · day as part of an elemental diet. After 1-day adaptation to the test diet, [C]bicarbonate and L-[1-C]phenylalanine tracers were given enterally. Breath samples were collected at baseline and during isotopic plateaus. The mean tryptophan requirement was determined by using the biphasic linear regression crossover analysis on the fraction of CO2 recovery from L-[1-C]phenylalanine oxidation (FCO2). Data are presented as mean ± standard deviation., Results: A total of 30 term neonates (gestational age 39 ± 1 weeks) were studied at 9 ± 4 days. FCO2 decreased until a tryptophan intake of 15 mg · kg · day; additional increases in tryptophan intake did not affect FCO2. Mean requirement was determined to be 15 mg · kg · day., Conclusions: The mean tryptophan requirement for elemental formula-fed term infants is 15 mg · kg · day. This requirement is lower than the present recommended intake of 29 mg · kg · day, which is based on the average intake of a breastfed infant.

Background: Knowledge of essential amino acid requirements in infants is important because excessive intake of protein can lead to increased long-term morbidity such as obesity. A deficient intake may lead to suboptimal growth and impaired neurodevelopment. The current recommended branched-chain amino acid requirements in infants aged 0-1 mo are based on the amino acid content of human milk., Objective: We quantified the requirements for isoleucine, leucine, and valine for term neonates by using the indicator amino acid oxidation method with [1-(13)C]phenylalanine as the indicator., Design: Fully enterally fed term infants received randomly graded amounts of isoleucine (5-216 mg · kg(-1) · d(-1)), leucine (5-370 mg · kg(-1) · d(-1)), or valine (5-236 mg · kg(-1) · d(-1)) as part of an elemental formula. Data are expressed as means ± SDs., Results: Eighty-three Asian, term neonates (mean ± SD birth weight: 3.3 ± 0.4 kg; gestational age: 39.4 ± 1.3 wk) were studied at a postnatal age of 13 ± 5 d. Mean requirements for isoleucine, leucine, and valine (measured in boys only) were 105 mg · kg(-1) · d(-1) (r(2) = 0.61, P < 0.001), 140 mg · kg(-1) · d(-1) (r(2) = 0.26, P < 0.01), and 110 mg · kg(-1) · d(-1) (r(2) = 0.35, P = 0.001), respectively., Conclusions: Current human milk-based recommendations for isoleucine and valine in term infants aged 0-1 mo are correct. However, the current recommendation for leucine (166 mg · kg(-1) · d(-1)) is higher than the mean requirement of 140 mg · kg(-1) · d(-1) that we determined in this study. This trial was registered at www.trialregister.nl as NTR1610.

The goal of pediatricians involved in the nutritional management of preterm infants is to mimic intrauterine growth and to obtain a functional outcome comparable to that for infants born at term. Appropriate administration of nutrients in the first few days to weeks of life will reduce the growth restriction that is frequently observed. Existing guidelines advise providing preterm infants with both amino acids and lipids from birth onward. Despite this knowledge, many hospital units do not comply with these guidelines. Further improvement of the quality of the composition of parenteral solutions for both neonates as well as older children should be the subject of further research.

Functional outcome of preterm infants is highly related to the quality and quantity of nutrients provided during the first few weeks of life. New guidelines, as published by the ESPGHAN in 2010, have provided means to prevent undernutrition in the NICU. Especially proteins and amino acids seem to play a pivotal role, and the optimal regimen has not yet been determined. New data on the intrauterine nutrient supply suggest a high amino acid intake during the fetal period. How these results might translate into improvement of especially neurocognitive outcome needs to be investigated., (Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel.)

Background: Infant nutrition has a major impact on child growth and functional development. Low and high intakes of protein or amino acids could have a detrimental effect., Objective: The objective of the study was to determine the lysine requirement of enterally fed term neonates by using the indicator amino acid oxidation (IAAO) method. L-[1-(13)C]phenylalanine was used as an indicator amino acid., Design: Twenty-one neonates were randomly assigned to lysine intakes that ranged from 15 to 240 mg · kg(-1) · d(-1). Breath, urine, and blood samples were collected at baseline and during the plateau. The mean lysine requirement was determined by using biphasic linear regression crossover analysis on the fraction of (13)CO(2) recovery from L-[1-(13)C]phenylalanine oxidation (F(13)CO(2)) and phenylalanine oxidation rates calculated from the L-[1-(13)C]phenylalanine enrichment of urine and plasma., Results: The mean (±SD) phenylalanine flux calculated from urine and plasma L-[1-(13)C]phenylalanine enrichment data were 88.3 ± 6.9 and 84.5 ± 7.4 μmol · kg(-1) · h(-1), respectively. Graded intakes of lysine had no effect on phenylalanine fluxes. The mean lysine requirement determined by F(13)CO(2) was 130 mg · kg(-1) · d(-1) (upper and lower CIs: 183.7 and 76.3 mg · kg(-1) · d(-1), respectively). The mean requirement was identical to the requirement determined by using phenylalanine oxidation rates in urine and plasma., Conclusions: The mean lysine requirement of enterally fed term neonates was determined by using F(13)CO(2) and phenylalanine oxidation rates calculated from the L-[1-(13)C]phenylalanine enrichment of urine and plasma. These methods yielded a similar result of 130 mg lysine · kg(-1) · d(-1). This study demonstrates that sampling of (13)CO(2) in expired air is sufficient to estimate the lysine requirement by using the IAAO method in infants. This trial was registered at www.trialregister.nl as NTR1610.

Background: Despite nutritional intervention, albumin concentrations are often low in critically ill premature neonates., Objective: Our aim was to quantify albumin synthesis rates during early life under physiologic circumstances. Human fetuses thereby reflect the developmentally related optimal condition., Design: Pregnant women undergoing elective cesarean delivery received 3 different labeled amino acid infusions starting at different times before surgery. With the use of mass spectrometry techniques, this novel model enabled us to quantify fetal albumin synthesis from a single blood sample taken from the umbilical cord after cesarean delivery. The fractional synthesis rate reflects the fraction of the albumin pool that is daily renewed. The absolute synthesis rate is the absolute amount of albumin that is daily synthesized. Results are expressed as medians (25th-75th percentile)., Results: We studied 8 fetuses at 29.9 (28.4-35.4) weeks of gestation and 8 fetuses around term. Fractional synthesis rates in premature fetuses [17.5 (12.1-24.4) %/d] were higher (P = 0.02) than in mature fetuses [10.4 (9.1-13.7) %/d]. Absolute synthesis rates were also higher (P = 0.02) in premature than in mature fetuses: 280 (227-365) versus 205 (184-238) mg . kg(-1) . d(-1)., Conclusions: On a weight basis, albumin synthesis rates in premature fetuses were higher than in fetuses at term and were higher than the rates previously found in neonates after preterm birth. Considering that the premature fetal liver can synthesize albumin at a high rate, the observed hypoalbuminemia in premature infants therefore seems to suggest that current (nutritional) therapies fail to meet requirements necessary to sustain optimum albumin synthesis rates.

Objective: Optimal nutrition is of utmost importance for the preterm infant's later health and developmental outcome. Amino acid requirements for preterm infants differ from those for term and older infants, because growth rates differ. Some nonessential amino acids, however, cannot be sufficiently synthesized endogenously. Cyst(e)ine is supposed to be such a conditionally essential amino acid in preterm infants. The objective of this study was to determine, at 32 and 35 weeks' postmenstrual age, cyst(e)ine requirements in fully enterally fed very low birth weight preterm infants with gestational ages of <29 weeks., Methods: Infants were randomly assigned to 1 of the 5 graded cystine test diets that contained generous amounts of methionine. Cyst(e)ine requirement was determined with the indicator amino acid oxidation technique ([1-(13)C]phenylalanine) after 24-hour adaptation., Results: Fractional [1-(13)C]phenylalanine oxidation was established in 47 very low birth weight preterm infants (mean gestational age: 28 weeks +/- 1 week SD; birth weight: 1.07 kg +/- 0.21 kg SD). Increase in dietary cyst(e)ine intake did not result in a decrease in fractional [1-(13)C]phenylalanine oxidation., Conclusions: These data do not support the hypothesis that endogenous cyst(e)ine synthesis is limited in very low birth weight preterm infants with gestational ages of <29 weeks, both at 32 and 35 weeks postmenstrual age. It is safe to conclude that cyst(e)ine requirement is <18 mg/kg per day in enterally fed very low birth weight preterm infants who are older than 32 weeks' postmenstrual age and whose methionine intake is adequate. Therefore, cyst(e)ine is probably not a conditionally essential amino acid in these infants.

Background: Cyst(e)ine can be synthesized de novo from methionine and serine and is, therefore, a nonessential amino acid in human adults. Several studies have suggested that cyst(e)ine might be a conditionally essential amino acid in preterm infants because of biochemical immaturity. No data are available on cyst(e)ine requirements in low-birth-weight (LBW) preterm infants., Objective: The aim was to determine cyst(e)ine requirements in LBW infants with gestational ages from 32 to 34 wk, measured 1 mo after birth with the use of the indicator amino acid oxidation technique., Design: LBW infants were randomly assigned to 1 or 2 of the 5 formulas containing graded cystine concentrations (11, 22, 32, 43, or 65 mg cyst(e)ine/100 mL) and generous amounts of methionine. After 24-h adaptation, cyst(e)ine requirement was determined by (13)CO(2) release from [1-(13)C]phenylalanine in expired breath. (13)CO(2) enrichment was measured by isotopic ratio mass spectrometry., Results: Cyst(e)ine requirement was determined in 25 LBW infants with a mean (+/-SD) gestational age of 33 +/- 1 wk and birth weight of 1.78 +/- 0.32 kg. Fractional oxidation of [1-(13)C]phenylalanine did not differ between the 5 groups., Conclusions: There is no evidence for limited endogenous cyst(e)ine synthesis in 4-wk-old LBW preterm infants born at gestational ages from 32 to 34 wk. It is safe to conclude that the cyst(e)ine requirement is <18 mg kg(-1) d(-1) providing generous amounts of methionine and that cyst(e)ine is probably not a conditionally essential amino acid in fully enterally fed LBW preterm infants born at 32-34 wk.

Purpose of Review: The prevalence of malnutrition among children admitted to a pediatric intensive care unit is still high. Assessment of nutrient supply is essential in the care of critically ill children because inadequate nutrition can increase morbidity and mortality. This review covers the causes and consequences of inadequate nutrient supply to critically ill children., Recent Findings: A major factor contributing to the cause of inadequate nutrient supply is the difficulty in estimating nutritional needs of the individual child. Reasonable values for energy expenditure can be derived from prediction formulae but measuring energy expenditure by indirect calorimetry is useful in selected cases. Furthermore, under-prescription and inadequate delivery of nutrients caused by fluid volume restriction, procedural interruptions or cessation because of gastrointestinal intolerance or mechanical problems cause additional nutritional deficits. As routine nutritional assessment is lacking in many pediatric intensive care units, the ability to monitor the adequacy of nutritional support is poor., Summary: In the majority of children admitted to a pediatric intensive care unit, nutritional problems--both underfeeding and overfeeding--occur during admission due to poor estimation of nutritional needs, under-prescribing and problems in the delivery of the nutrients. Recommendations are made in order to prevent inadequate nutritional supply and its potentially harmful consequences in critically ill children.

The portal-drained viscera (stomach, intestine, pancreas and spleen) have a much higher rate of both energy expenditure and protein synthesis than can be estimated on the basis of their weight. A high utilization rate of dietary nutrients by the portal-drained viscera might result in a low systemic availability which determines whole-body growth. From studies in our multiple catheterized piglet model, we conclude that more than half of the dietary protein intake is utilized within the portal-drained viscera and that amino acids are a major fuel source for the visceral organs. Specific stable isotope studies reveal that there are large differences in the utilization rate amongst the different amino acids. The majority of the results obtained from the piglet studies can be extrapolated to the human (preterm) infant. First-pass, splanchnic uptake of lysine and threonine differ substantially, while non-essential amino acids are oxidized to a great extend in the human gut. Overall, these studies indicate that gut amino acid metabolism has a great impact on systemic availability and hence growth in the neonate.

Background and Aims: Nutritional support is essential in the care of critically ill children since inadequate feeding increases morbidity and negatively affects growth. We aimed to compare cumulative energy and protein intakes with recommended dietary intakes (RDA) and examine relationships between accumulated balances and anthropometric parameters., Methods: Prospective, observational study. Total daily energy and protein intakes were determined during a maximum of 14 days in 261 children admitted to our multidisciplinary tertiary pediatric ICU. Actual intakes were subtracted from RDA and cumulative balances were calculated. Relations between cumulative balances, various clinical factors and changes in anthropometry (weight, arm and calf circumference) were analyzed using regression analysis., Results: At 14 days after admission children showed significant cumulative nutritional deficits compared to RDA. These deficits were on average 27, 20, 12 kcal/kg and 0.6, 0.3, and 0.2 g protein/kg per day for preterm neonates (n = 103), term neonates (n = 91) and older children (n = 67), respectively. Age at admission, length of ICU-stay and days on mechanical ventilation were negatively related to cumulative balances. Cumulative energy and protein deficits were associated with declines in SD-scores for weight and arm circumference., Conclusions: Children admitted to the ICU accumulate substantial energy and protein deficits when compared to RDA. These deficits are related to decreases in anthropometric parameters.

Background: What is the appropriate time to start complementary feeding for preterm infants? The answer to this question is yet under debate. The timing of initiating complementary feeding may be associated with overweight in term infants. This systematic review aimed to study the effect of the timing of initiating complementary feeding on overweight in preterm infants. Predefined search items included preterm infants, complementary feeding, overweight, and their synonyms. Summary: The search identified 15,749 articles, of which 5 articles were included. Three studies presented data of randomized controlled trials and 2 studies were cohort studies. Two randomized controlled trials found no significant difference in body mass index (BMI) Z-score between the intervention groups at 12 months of age. One randomized controlled trial presented a significant greater mean rate of growth in length per week until 12 months in the preterm weaning strategy-group compared with the current best practices. One observational study concluded that each month the infants received complementary food later, the Z-score for length and weight was reduced by 0.1. Key Messages: No clear conclusion could be drawn from the included studies. This review illustrates the need for further research to access the effect of the timing of initiating complementary feeding on overweight in preterm infants. [ABSTRACT FROM AUTHOR]

As technology has advanced, survival rates of preterm infants have improved dramatically. Human milk was the primary source of enteral nutrition during the early days of neonatology, but the HIV/AIDS epidemic resulted in an increased use of preterm formula. More recently, the benefits of human milk were rediscovered, resulting in increased use of donor human milk as well. The awareness that human milk does not contain the amounts of nutrients to meet the high requirements of infants born premature resulted in the development of human milk fortifiers. The development of these fortifiers is still ongoing, as are alternative methods of pasteurization of donor milk. Those initiatives will increase the use of human milk with consequently short- and long-term benefits for preterm infants. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Background: The essential amino acid methionine can be used for protein synthesis but also serves as a precursor for homocysteine and cysteine. Objective: The objective of this study was to determine the minimal obligatory methionine requirement of infants in the presence of excess cysteine (91 mg · kg-1 · d -1) by using the indicator amino acid oxidation (IAAO) method with L-[1 -13C]phenylalanine as the indicator. Design: Fully enterally fed term infants < 1 mo of age were randomly assigned to methionine intakes that ranged from 3 to 59 mg • kg-1 · d-1 as part of an elemental formula. After 1 d of adaptation to the test diet, [l3C]bicarbonate and L-[1-13C]phenylalanine tracers were given enterally. Breath samples were collected at baseline and during isotopic plateaus. The mean methionine requirement was determined by using biphasic linear regression crossover analysis on the fraction of 13CO2 recovery from L-[1-13C]phenylalanine oxidation (F13CO2). Data are presented as means ± SDs. Results: Thirty-three neonates (gestational age: 39 ± 1 wk) were studied at 13 ± 6 d. With increasing methionine intakes, F13CO2 decreased until a methionine intake of 38 mg • kg~' · d-1; additional increases in methionine intake did not affect FI3CO2. The mean methionine requirement was determined at 38 mg • kg-1 • d-1, and the upper and lower CIs were 48 and 27 mg • kg-1 • d-1, respectively (P < 0.0001, r = 0.59). Conclusions: Although the current recommended methionine intake of 28 mg • kg-1 • d-1 is within the CIs of our study, the estimated mean requirement is substantially higher. However, most of the infant formulas provide a methionine intake of 49-80 mg · kg-1 • d-1, which is above the upper CI of our study. This trial was registered at www.trialregister.nl as NTR1610. [ABSTRACT FROM AUTHOR]