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Controversy exists in clinical practice regarding optimal initial enteral feeding (EF) for moderately premature and low birth weight (BW) infants. We included 96 infants stratified into 3 groups (I: 1600-1799 g [n = 22]; II: 1800-1999 g [n = 42]; III: 2000-2200 g [n = 32]). The protocol recommended starting with minimal EF (MEF) in infants weighing

Objective(s): To investigate the predictive performances of exhaled breath volatile organic compounds (VOCs) for development of bronchopulmonary dysplasia (BPD) in infants born preterm. Methods: Exhaled breath was collected from infants born

BACKGROUND OBJECTIVES: Human milk (HM) is better tolerated than formula in preterm infants. Insulin, which is naturally present in HM but not in formula, has been suggested as a key factor for feeding tolerance, as it appears to stimulate intestinal maturation. Its precise concentrations during the early postnatal period, however, remains unknown. The objective of this study was to assess the natural timecourse of the HM insulin concentration during the first ten days postpartum. The effect of preterm delivery, maternal obesity, and diurnal rhythm were also assessed. METHOD: HM was collected from 31 non-diabetic mothers (21 preterm [gestational age (GA)

Objectives: To review the current literature and develop consensus conclusions and recommendations on nutrient intakes and nutritional practice in preterm infants with birthweight 90% consensus was not achieved, online discussion meetings were held, along with further voting until agreement was reached. Results: In general, there is a lack of strong evidence for most nutrients and topics. The summary paper is supported by additional supplementary digital content that provide a fuller explanation of the literature and relevant physiology: introduction and overview; human milk reference data; intakes of water, protein, energy, lipid, carbohydrate, electrolytes, minerals, trace elements, water soluble vitamins, and fat soluble vitamins; feeding mode including mineral enteral feeding, feed advancement, management of gastric residuals, gastric tube placement and bolus or continuous feeding; growth; breastmilk buccal colostrum, donor human milk, and risks of cytomegalovirus infection; hydrolyzed protein and osmolality; supplemental bionutrients; and use of breastmilk fortifier. Conclusions: We provide updated ESPGHAN CoN consensus-based conclusions and recommendations on nutrient intakes and nutritional management for preterm infants.

Feeding preterm infants with mother’s own milk is associated with a reduction in postnatal complications and an improved neurocognitive outcome. Therefore, the bioactive factor composition of human milk has been used as a tool for the development of nutritional supplements with a potential prophylactic or therapeutic effect. The aim of this systematic review was to provide an overview on bioactive factors which have been studied as supplement to enteral nutrition in randomized controlled trials, and to provide an overview of ongoing trials. MEDLINE, EMBASE, CENTRAL, and clinical trial registers were searched. Studies on the antimicrobial protein lactoferrin were excluded as these were summarized very recently in three separate systematic reviews. Studies on vitamins D, K and iron were also excluded as they are already incorporated in most international guidelines. We identified 17 different bioactive factors, which were investigated in 26 studies. Despite the encouraging potential effects of several bioactive factors, more high-quality studies with a sufficient number of preterm infants are required before a certain factor may be implemented into clinical practice. Three large trials (n > 500) that investigate the effects of either enteral insulin or vitamin A are currently ongoing and could provide more definite answers on these specific supplements.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism, characterized by increased endogenous oxalate production. The metabolic pathways underlying oxalate synthesis have not been fully elucidated, and upcoming therapies require more reliable outcome parameters than the currently used plasma oxalate levels and urinary oxalate excretion rates. We therefore developed a stable isotope infusion protocol to assess endogenous oxalate synthesis rate and the contribution of glycolate to both oxalate and glycine synthesis in vivo. METHODS: Eight healthy volunteers and eight patients with PH1 (stratified by pyridoxine responsiveness) underwent a combined primed continuous infusion of intravenous [1-(13)C]glycolate, [U-(13)C(2)]oxalate, and, in a subgroup, [D(5)]glycine. Isotopic enrichment of (13)C-labeled oxalate and glycolate were measured using a new gas chromatography–tandem mass spectrometry (GC-MS/MS) method. Stable isotope dilution and incorporation calculations quantified rates of appearance and synthetic rates, respectively. RESULTS: Total daily oxalate rates of appearance (mean [SD]) were 2.71 (0.54), 1.46 (0.23), and 0.79 (0.15) mmol/d in patients who were pyridoxine unresponsive, patients who were pyridoxine responsive, and controls, respectively (P=0.002). Mean (SD) contribution of glycolate to oxalate production was 47.3% (12.8) in patients and 1.3% (0.7) in controls. Using the incorporation of [1-(13)C]glycolate tracer in glycine revealed significant conversion of glycolate into glycine in pyridoxine responsive, but not in patients with PH1 who were pyridoxine unresponsive. CONCLUSIONS: This stable isotope infusion protocol could evaluate efficacy of new therapies, investigate pyridoxine responsiveness, and serve as a tool to further explore glyoxylate metabolism in humans.

Human milk (HM) contains numerous non-nutritive bioactive factors, amongst which the peptide hormone insulin. HM insulin has been suggested to accelerate intestinal maturation, thereby promoting feeding tolerance. Therefore, recombinant human insulin for enteral administration has been developed which might serve as supplement to HM or formula for preterm infants. However, the natural course of the HM insulin concentration directly following delivery is unknown, which hampers the development of dosage schedules in clinical trials. The aim of this study was to validate a method for insulin determination in small volumes of HM, and to assess the stability of HM insulin. The results showed that the HM insulin concentration can be measured rapidly and reliably by using an automated immunoassay. In addition, HM insulin is stable at 4 °C for at least 72 h, at room temperature for a maximum of 12 h, at −20 °C for at least 2.5 years, and during at least five freeze-thaw cycles.

More than 10,000 preterm infants have participated in randomised controlled trials on probiotics worldwide, suggesting that probiotics in general could reduce rates of necrotising enterocolitis (NEC), sepsis, and mortality. Answers to relevant clinical questions as to which strain to use, at what dosage, and how long to supplement are, however, not available. On the other hand, an increasing number of commercial products containing probiotics are available from sometimes suboptimal quality. Also, a large number of units around the world are routinely offering probiotic supplementation as the standard of care despite lacking solid evidence. Our recent network meta-analysis identified probiotic strains with greatest efficacy regarding relevant clinical outcomes for preterm neonates. Efficacy in reducing mortality and morbidity was found for only a minority of the studied strains or combinations. In the present position paper, we aim to provide advice, which specific strains might potentially be used and which strains should not be used. In addition, we aim to address safety issues of probiotic supplementation to preterm infants, who have reduced immunological capacities and occasional indwelling catheters. For example, quality reassurance of the probiotic product is essential, probiotic strains should be devoid of transferable antibiotic resistance genes, and local microbiologists should be able to routinely detect probiotic sepsis. Provided all safety issues are met, there is currently a conditional recommendation (with low certainty of evidence) to provide either Lactobacillus rhamnosus GG ATCC53103 or the combination of Bifidobacterium infantis Bb-02, Bifidobacterium lactis Bb-12, and Streptococcus thermophilus TH-4 in order to reduce NEC rates.

ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Lipids

High rates of oxidative stress are common in preterm born infants and have short- and long-term consequences. The antioxidant properties of human milk limits the consequences of excessive oxidative damage. However, as the mother’s own milk it is not always available, donor milk may be provided as the best alternative. Donor milk needs to be pasteurized before use to ensure safety. Although pasteurization is necessary for safety reasons, it may affect the activity and concentration of several biological factors, including antioxidants. This literature review describes the effect of different pasteurization methods on antioxidant properties of human milk and aims to provide evidence to guide donor milk banks in choosing the best pasteurization method from an antioxidant perspective. The current literature suggests that Holder pasteurization reduces the antioxidant properties of human milk. Alternative pasteurization methods seem promising as less reduction is observed in several studies.

Proteins are key structural components of all human cells and are also involved in key physiologic processes through their roles as enzymes, hormones and transport proteins. Protein requirements are substantially higher in preterm infants than those born at term, yet inadequate protein intakes are a common problem on many neonatal units. Very preterm infants (VPT

Summary Background & aims Albumin is one of the most important plasma proteins and plays a key role in many physiologic processes, such as preserving colloid osmotic pressure, scavenging radicals, and binding and transporting bilirubin, hormones, and drugs. However, albumin concentrations are often low in preterm infants during the first days of life. We hypothesized that early parenteral lipid and high-dose amino acid (AA) administration to very low birth weight (VLBW) infants from birth onwards increases hepatic albumin synthesis rates. Methods Inborn VLBW infants were randomized to receive from birth onwards either 2.4 g amino acids/(kg · d) (control group), 2.4 g amino acids/(kg · d) plus 2 g lipids/(kg · d) (AA + lipid group), or 3.6 g amino acids/(kg · d) plus 2 g lipids/(kg · d) (high AA + lipid group). On postnatal day 2, infants received a primed continuous infusion of [U- 13 C 6 , 15 N]leucine. Mass spectrometry was used to determine the fractional and absolute albumin synthesis rates (FSR and ASR, respectively). Results In total, 28 infants (median gestational age 27 weeks (IQR 25–28), median birth weight 810 g (IQR 679–998) were studied. The median FSR was 6.5%/d in the control group, 10.6%/d in the AA group, and 12.3%/d in the high AA + lipid group, while the median was 84 mg/(kg · d) in the control group, 138 mg/(kg · d) in the AA group, and 160 mg/(kg · d) in the high AA + lipid group. Conclusion A group of VLBW infants given parenteral nutrition containing lipids and high-dose amino acids showed a higher rate of albumin synthesis compared to infants receiving no lipids and standard amounts of amino acids during the first two days of life.

BACKGROUND: Nutrient fortification of human milk is often required to secure adequate growth and organ development for very preterm infants. There is concern that formula-based fortifiers (FFs) induce intestinal dysfunction, feeding intolerance, and necrotizing enterocolitis (NEC). Bovine colostrum (BC) may be an alternative nutrient fortifier, considering its high content of protein and milk bioactive factors.OBJECTIVE: We investigated whether BC was superior to an FF product based on processed bovine milk and vegetable oil to fortify donor human milk (DHM) for preterm pigs, used as a model for infants.METHODS: Sixty preterm pigs from 4 sows (Danish Landrace × Large White × Duroc, birth weight 944 ± 29 g) received decreasing volumes of parenteral nutrition (96-72 mL ⋅ kg-1 ⋅ d-1) and increasing volumes of enteral nutrition (24-132 mL ⋅ kg-1 ⋅ d-1) for 8 d. Pigs were fed donor porcine milk (DPM) and DHM with or without FF or BC fortification (+4.6 g protein ⋅ kg-1 ⋅ d-1).RESULTS: DPM-fed pigs showed higher growth (10-fold), protein synthesis (+15-30%), villus heights, lactase and peptidase activities (+30%), and reduced intestinal cytokines (-50%) relative to DHM pigs (all P < 0.05). Fortification increased protein synthesis (+20-30%), but with higher weight gain and lower urea and cortisol concentrations for DHM+BC compared with DHM+FF pigs (2- to 3-fold differences, all P ≤ 0.06). DHM+FF pigs showed more diarrhea and reduced lactase and peptidase activities, hexose uptake, and villus heights relative to DHM+BC or DHM pigs (30-90% differences, P < 0.05). Fortification did not affect NEC incidence but DHM+BC pigs had lower colonic interleukin (IL)-6 and IL-8 concentrations relative to the remaining pigs (-30%, P = 0.06). DHM+FF pigs had higher stomach bacterial load than did DHM, and higher bacterial density along intestinal villi than did DHM and DHM+BC pigs (2- to 3-fold, P < 0.05).CONCLUSIONS: The FF product investigated in this study reduced growth, intestinal function, and protein utilization in DHM-fed preterm pigs, relative to BC as fortifier. The relevance of BC as an alternative nutrient fortifier for preterm infants should be tested.

Several reports have investigated amino acid administration in premature infants during the early postnatal phase. Most of these previous studies, however, have only evaluated short-term in-hospital outcomes. Our aim was to describe long-term outcomes in premature infants previously subjected to different nutritional regimens in a randomized controlled trial. The primary outcome was survival without major disabilities, and the secondary outcomes included anthropometry and mental development. Infants born

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.

The use of stable isotopes combined with mass spectrometry (MS) provides insight into metabolic processes within the body. Herein, an overview on the relevance of stable isotope methodology in pediatric research is presented. Applications for the use of stable isotopes with MS cover carbohydrate, fat, and amino acid metabolism as well as body composition, energy expenditure, and the synthesis of specific peptides and proteins, such as glutathione and albumin. The main focus of these studies is on the interactions between nutrients and the endogenous metabolism within the body and how these factors affect the health of a growing infant. Considering that the early imprinting of metabolic processes hugely impacts metabolism (and thus functional outcome) later in life, research in this area is important and is advancing rapidly. The major fluxes on a metabolic level are the synthesis and breakdown rates. They can be quantified using kinetic tracer analysis and mathematical modeling. Organic MS and isotope ratio mass spectrometry (IRMS) are the two most mature techniques for the isotopic analysis of compounds. Introduction of the samples is usually done by coupling gas chromatography (GC) to either IRMS or MS because it is the most robust technique for specific isotopic analysis of volatile compounds. In addition, liquid chromatography (LC) is now being used more often as a tool for sample introduction of both volatile and non-volatile compounds into IRMS or MS for (13)C isotopic analyses at natural abundances and for (13)C-labeled enriched compounds. The availability of samples is often limited in pediatric patients. Therefore, sample size restriction is important when developing new methods. Also, the availability of stable isotope-labeled substrates is necessary for measurements of the kinetics and concentrations in metabolic studies, which can be a limiting factor. During the last decade, the availability of these substrates has increased. Furthermore, improvements in the accuracy, precision, and sensitivity of existing techniques (such as GC/IRMS) and the development of new techniques (such as LC/IRMS) have opened up new avenues for tackling these limitations.

Human fetal metabolism is largely unexplored. Understanding how a healthy fetus achieves its fast growth rates could eventually play a pivotal role in improving future nutritional strategies for premature infants. To quantify specific fetal amino acid kinetics, eight healthy pregnant women received before elective cesarean section at term, continuous stable isotope infusions of the essential amino acids [1-(13)C,(15)N]leucine, [U-(13)C(5)]valine, and [1-(13)C]methionine. Umbilical blood was collected after birth and analyzed for enrichments and concentrations using mass spectrometry techniques. Fetuses showed considerable leucine, valine, and methionine uptake and high turnover rates. alpha-Ketoisocaproate, but not alpha-ketoisovalerate (the leucine and valine ketoacids, respectively), was transported at net rate from the fetus to the placenta. Especially, leucine and valine data suggested high oxidation rates, up to half of net uptake. This was supported by relatively low alpha-ketoisocaproate reamination rates to leucine. Our data suggest high protein breakdown and synthesis rates, comparable with, or even slightly higher than in premature infants. The relatively large uptakes of total leucine and valine carbon also suggest high fetal oxidation rates of these essential branched chain amino acids. (Pediatr Res 70: 566-571, 2011)

Purpose of review: Obviously, the ultimate goal in neonatology is to achieve a functional outcome in premature infants that is comparable to healthy term-born infants. As nutrition is one of the key factors for normal cell growth, providing the right amount and quality of nutrients could prove pivotal for normal development. However, many premature infants are catabolic during the first week of life, which has directly been linked to growth failure, disease, and suboptimal long-term outcome. This review describes the progress in research on parenteral nutrition for premature infants with a focus on amino acids and the influence of nutrition on later outcome. Recent findings: Although randomized clinical trials on early nutrition for premature infants remain relatively sparse, evidence is accumulating on its beneficial effects both on the short-term and long-term. However, some research also warns for adverse effects. Summary: Despite the fact that substantially improved nutritional therapies for preterm neonates have been implemented, still, some reluctance exists when it comes to providing high amounts of nutrition to the most immature infants. Pros and cons are outlined, as well as deficits in knowledge, when it comes to providing the optimal nutrient strategy in the first postnatal phase.

PURPOSE OF REVIEW: Premature infants often suffer from suboptimal outcome, at least partially due to suboptimal nutrition. Gaining insight into human fetal amino acid metabolism might ultimately lead to an improved nutritional strategy for prematurely born infants. Our aim was, therefore, to discuss recent findings with regard to human fetal amino acid metabolism. RECENT FINDINGS: Human fetal protein and amino acid metabolism can be studied in vivo using stable isotope techniques. To date, however, only a few studies employing these techniques have been performed. For one, it was shown in vivo that essential amino acids are transported at different rates across the human placenta. In addition, tyrosine appears not to be a conditionally essential amino acid in the fetus at term, as phenylalanine is hydroxylated into tyrosine at considerable rates. Furthermore, albumin is synthesized at very high rates at two-thirds of gestation; higher than prematurely born infants do at a neonatal intensive care unit. This could indicate that postnatal nutrition of very immature infants can be improved. SUMMARY: Although technically challenging, more studies regarding human fetal amino acid metabolism should be performed. Premature infants could then benefit from this knowledge from new nutritional strategies.

The use of stable isotope labelled glucose provides insight into glucose metabolism. The 13C-isotopic enrichment of glucose is usually measured by gas chromatography/mass spectrometry (GC/MS) or gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). However, in both techniques the samples must be derivatized prior to analysis, which makes sample preparation more labour-intensive and increases the uncertainty of the measured isotopic composition. A novel method for the determination of isotopic enrichment of glucose in human plasma using liquid chromatography/isotope ratio mass spectrometry (LC/IRMS) has been developed. Using this technique, for which hardly any sample preparation is needed, we showed that both the enrichment and the concentration could be measured with very high precision using only 20 µL of plasma. In addition, a comparison with GC/MS and GC/IRMS showed that the best performance was achieved with the LC/IRMS method making it the method of choice for the measurement of 13C-isotopic enrichment in plasma samples. Copyright © 2009 John Wiley & Sons, Ltd.

Background: We recently showed that parenteral administration of amino acids to premature infants immediately after birth is safe and results in a positive nitrogen balance and increased whole-body protein synthesis. However, we did not determine organ-specific effects; albumin, produced by the liver, is an important protein, but its concentration is often low in premature neonates during the first few days after birth. Objective: The objective of the study was to test the hypothesis that the fractional and absolute albumin synthesis rates would increase with the administration of amino acids after birth, even at low nonprotein energy intake. Design: Premature infants (-1 · d-1 (intervention group, n = 8). On postnatal day 2, all infants received a primed continuous infusion of [1-13C]leucine, and mass spectrometry techniques were used to determine the incorporation of the leucine into albumin. Results are expressed as medians and 25th and 75th percentiles. Results: Albumin fractional synthesis rates in the intervention group were significantly higher than those in the control group [22.9% (17.6-28.0%)/d and 12.6% (11.0-19.4%)/d, respectively; P = 0.029]. Likewise, the albumin absolute synthesis rates in the intervention group were significantly higher than those in the control group [228 (187-289) mg · kg-1 · d -1 and 168 (118-203) mg · kg-1 · d -1, respectively; P = 0.030]. Conclusion: Amino acid administration increases albumin synthesis rates in premature neonates even at a low energy intake.

Very-low-birth-weight (VLBW) infants are dependent on parenteral nutrition after birth. A parenteral lipid emulsion with a multicomponent composition may improve growth and neurodevelopment and may prevent liver injury, which is often observed in association with long-term parenteral nutrition with pure soybean oil. Our aim was to evaluate the safety and efficacy of a multicomponent lipid emulsion containing 30% soybean oil, 30% medium-chain triacylglycerol, 25% olive oil, and 15% fish oil compared with a conventional pure soybean oil emulsion in VLBW infants. We conducted a double-blind randomized controlled trial in VLBW infants randomized to parenteral nutrition with the multicomponent (study group) or pure soybean oil emulsion (control group) from birth at a dose of 2 to 3 g · kg(-1) · day(-1) until the infants were receiving full enteral nutrition. We assessed efficacy by growth rates and measuring plasma fatty acid profiles (representative subset). Safety was evaluated by assessing hematologic and biochemical parameters, potentially harmful phytosterol concentrations (same subset), and clinical neonatal outcome parameters. Ninety-six infants were included (subsets n = 21). The multicomponent emulsion was associated with higher weight and head circumference z scores during admission. Plasma eicosapentaenoic acid and docosahexaenoic acid concentrations were higher in the study group. The hematological, biochemical, and neonatal outcomes were not different between groups, whereas the plasma concentrations of phytosterols were higher in the control group. The multicomponent lipid emulsion was well tolerated and associated with improved growth and higher plasma fatty acid profiles in VLBW infants in comparison with the pure soybean oil emulsion

Amino acids and protein are key factors for growth. The neonatal period requires the highest intake in life to meet the demands. Those demands include amino acids for growth, but proteins and amino acids also function as signalling molecules and function as neurotransmitters. Often the nutritional requirements are not met, resulting in a postnatal growth restriction. However, current knowledge on adequate levels of both amino acid as well as protein intake can avoid under nutrition in the direct postnatal phase, avoid the need for subsequent catch-up growth and improve later outcome.

Summary Background & aims An anabolic state can be achieved upon intravenous amino acid administration during the immediate postnatal phase despite a low energy intake. The optimal dosing of amino acid and energy intake has yet to be established. The aim was to quantify the efficacy of early initiation of parenteral lipids and increased amounts of amino acids on metabolism and protein accretion in very low birth weight infants. Methods 28 very low birth weight infants were randomized to receive parenteral nutrition with glucose and either 2.4 g amino acids/(kg·d) (control group), 2.4 g amino acids/(kg·d) plus 2–3 g lipid/(kg·d) (AA + lipid group), or 3.6 g amino acids/(kg·d) plus 2–3 g lipid/(kg·d) (high AA + lipid group) from birth onward. On postnatal day 2, we performed a stable isotope study with [1- 13 C]phenylalanine, [ring-D 4 ]tyrosine, [U- 13 C 6 , 15 N]leucine, and [methyl-D 3 ]α-ketoisocaproic acid to quantify intermediate amino acid metabolism. Results The addition of lipids only had no effect on phenylalanine metabolism, whereas the addition of both lipids and additional amino acids increased the amount of phenylalanine used for protein synthesis. In addition, high amino acid intake significantly increased the rate of hydroxylation of phenylalanine to tyrosine, increasing the availability of tyrosine for protein synthesis. However, it also increased urea concentrations. Increasing energy intake from 40 to 60 kcal/(kg·d) did not increase protein efficiency as measured by phenylalanine kinetics. The leucine data were difficult to interpret due to the wide range of results and inconsistency in the data between the phenylalanine and leucine models. Conclusions High amino acid and energy intakes from birth onwards result in a more anabolic state in very low birth weight infants, but at the expense of higher urea concentrations, which reflects a higher amino acid oxidation. Long-term outcome data should reveal whether this policy deserves routine implementation. This trial was registered at www.trialregister.nl, trial number NTR1445, name Nutritional Intervention for Preterm Infants-2.

Background: The use of intravenous lipid emulsions in preterm infants has been limited by concerns regarding impaired lipid tolerance. As a result, the time of initiation of parenteral lipid infusion to very-low-birth-weight (VLBW) infants varies widely among different neonatal intensive care units. However, lipids provide energy for protein synthesis and supply essential fatty acids that are necessary for central nervous system development. Objective: The objective was to summarize the effects of initiation of lipids within the first 2 d of life and the effects of different lipid compositions on growth and morbidities in VLBW infants. Design: A systematic review and meta-analysis of publications identified in a search of PubMed, EMBASE, and Cochrane databases was undertaken. Randomized controlled studies were eligible if information on growth was available. Results: The search yielded 14 studies. No differences were observed in growth or morbidity with early lipid initiation. We found a weak favorable association of non-purely soybean-based emulsions with the incidence of sepsis (RR: 0.75; 95% CI: 0.56, 1.00). Conclusions: The initiation of lipids within the first 2 d of life in VLBW infants appears to be safe and well tolerated; however, beneficial effects on growth could not be shown for this treatment nor for the type of lipid emulsion. Emulsions that are not purely soybean oil-based might be associated with a lower incidence of sepsis. Large-scale randomized controlled trials in preterm infants are warranted to determine whether early initiation of lipids and lipid emulsions that are not purely soybean oil-based results in improved long-term outcomes. Am J Clin Nutr 2012;96:255-68

Recently, new guidelines for enteral feedings in premature infants were issued by the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition. Nevertheless, practice proves difficult to attain suggested intakes at all times, and occurrence of significant potential cumulative nutritional deficits ‘lies in wait’ in the neonatal intensive care unit. This review describes several aspects that are mandatory for optimizing nutritional intake in these vulnerable infants. These aspects range from optimal infrastructure to the initiation of parenteral nutrition with proper transition to enteral breast or formula feedings. Proper monitoring of nutritional tolerance includes serum biochemistry although proper specific markers are unknown and safety reference values are lacking. Although a lot of progress has been made through research during the last few decades, numerous questions still remain unanswered as to what would be the optimal quantity and quality of the various macronutrients. The inevitable suboptimal intake may, however, contribute significantly to the incidence of neonatal diseases, including impaired neurodevelopment. Therefore, it is pivotal that all hospital staff acknowledges that preterm birth is a nutritional emergency and that all must be done, both in clinical practice as well as in research, to reduce nutritional deficits.

Postnatal nutrition has a large impact on long-term outcome of preterm infants. Evidence is accumulating showing even a relationship between nutrient supply in the first week of life and later cognitive development in extremely low birth weight infants. Since enteral nutrition is often not tolerated following birth, parenteral nutrition is necessary. Yet, optimal parenteral intakes of both energy and amino acids are not well established. Subsequently, many preterm infants fail to grow well, with long-term consequences. Early and high dose amino acid administration has been shown to be effective and safe in very low birth weight infants, but the effect of additional lipid administration needs to be defined.

Background: Knowledge on human fetal amino acid (AA) metabolism, largely lacking thus far, is pivotal in improving nutritional strategies for prematurely born infants. Phenylalanine kinetics is of special interest as is debate as to whether neonates will adequately hydroxylate phenylalanine to the semiessential AA tyrosine. Objective: Our aim was to quantify human fetal phenylalanine and tyrosine metabolism. Design: Eight fasted, healthy, pregnant women undergoing elective cesarean delivery at term received primed continuous stable-isotope infusions of [1-C-13] phenylalanine and [ring-D-4] tyrosine starting before surgery. Umbilical blood flow was measured by ultrasound. Maternal and umbilical cord blood was collected and analyzed by gas chromatography-mass spectrometry for phenylalanine and tyrosine enrichments and concentrations. Data are expressed as medians (25th-75th percentile). Results: Women were in a catabolic state for which net fetal AA uptake was responsible for >= 25%. Maternal and fetal hydroxylation rates were 2.6 (2.2-2.9) and 7.5 (6.2-15.5) mu mol phenylalanine/(kg.h), respectively. Fetal protein synthesis rates were higher than breakdown rates: 92 (84-116) and 73 (68-87) lmol phenylalanine/(kg.h), respectively, which indicated an anabolic state. The median metabolized fraction of available phenylalanine and tyrosine in the fetuswas < 20% for both AAs. Conclusions: At term gestation, fetuses still show considerable net AA uptake and AA accretion [converted to tissue approximate to 12 g/(kg.d)]. The low metabolic uptake (AA usage) implies a very large nutritional reserve capacity of nutrients delivered through the umbilical cord. Fetuses at term are quite capable of hydroxylating phenylalanine to tyrosine. Am J Clin Nutr 2009; 89: 153-60.

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.

We previously showed that, in prematurely born infants, an anabolic state without metabolic acidosis can be achieved upon intravenous amino acid (AA) administration in the immediate postnatal phase, despite a low energy intake. We hypothesized that the anabolic state resulted from an increased protein synthesis and not a decreased proteolysis. Furthermore, we hypothesized that the energy needed for the higher protein synthesis rate would be derived from an increased glucose oxidation. To test our hypotheses, 32 ventilated premature infants (13C]leucine or [U- 13C 6]glucose. 13CO 2 enrichments in expiratory air and plasma [1- 13C]α-KICA (as an intracellular leucine precursor) and [U- 13C 6]glucose enrichments were measured by mass spectrometry techniques. The AA administration resulted in an increased incorporation of leucine into body protein and a higher leucine oxidation rate, whereas leucine release from proteolysis was not affected. Glucose oxidation rate did not increase upon AA administration. In conclusion, the anabolic state resulting from AA administration in the immediate postnatal period resulted from increased protein synthesis and not decreased proteolysis. The energy needed for the additional protein synthesis was not derived from an increased glucose oxidation.

Objectives: To test the hypothesis that the administration of 2.4 g amino acids (AA)/(kg·d) to very low birth weight infants is safe and results in a positive nitrogen balance. Study design: We conducted a randomized, clinical trial. Preterm infants with birth weights 2 tests were performed to compare groups. Results: Infants supplemented with AA had no major adverse side effects. Their blood urea nitrogen levels were higher, nitrogen balance turned positive upon AA administration, and more AA concentrations were within reference ranges. Conclusions: High-dose AA administration to very low birth weight infants can be introduced safely from birth onward and results in an anabolic state.

Objective To assess the efficacy and safety of early parenteral lipid and high-dose amino acid (AA) administration from birth onwards in very low birth weight (VLBW, birth weight Study design VLBW infants (n = 144; birth weight 862 ± 218 g; gestational age 27.4 ± 2.2 weeks) were randomized to receive 2.4 g of AA kg −1 ·d −1 (control group), or 2.4 g AA kg −1 ·d −1 plus 2-3 g lipids kg −1 ·d −1 (AA + lipid group), or 3.6 g AA kg −1 ·d −1 plus 2-3 g lipids kg −1 ·d −1 (high AA + lipid group) from birth onwards. The primary outcome was nitrogen balance. The secondary outcomes were biochemical variables, urea rate of appearance, growth rates, and clinical outcome. Results The nitrogen balance on day 2 was significantly greater in both intervention groups compared with the control group. Greater amounts of AA administration did not further improve nitrogen balance compared with standard AA dose plus lipids and was associated with high plasma urea concentrations and high rates of urea appearance. No differences in other biochemical variables, growth, or clinical outcomes were observed. Conclusions In VLBW infants, the administration of parenteral AA combined with lipids from birth onwards improved conditions for anabolism and growth, as shown by improved nitrogen balance. Greater levels of AA administration did not further improve the nitrogen balance but led to increased AA oxidation. Early lipid initiation and high-dose AA were well tolerated.