Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition.

The number of surviving children born prematurely has increased substantially during the last 2 decades. The major goal of enteral nutrient supply to these infants is to achieve growth similar to foetal growth coupled with satisfactory functional development. The accumulation of knowledge since the previous guideline on nutrition of preterm infants from the Committee on Nutrition of the European Society of Paediatric Gastroenterology and Nutrition in 1987 has made a new guideline necessary. Thus, an ad hoc expert panel was convened by the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition in 2007 to make appropriate recommendations. The present guideline, of which the major recommendations are summarised here (for the full report, see http://links.lww.com/A1480), is consistent with, but not identical to, recent guidelines from the Life Sciences Research Office of the American Society for Nutritional Sciences published in 2002 and recommendations from the handbook Nutrition of the Preterm Infant. Scientific Basis and Practical Guidelines, 2nd ed, edited by Tsang et al, and published in 2005. The preferred food for premature infants is fortified human milk from the infant's own mother, or, alternatively, formula designed for premature infants. This guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of approximately 1800 g, because most data are available for these infants. These recommendations are based on a considered review of available scientific reports on the subject, and on expert consensus for which the available scientific data are considered inadequate.

Adjustable fortification of human milk fed to preterm infants: does it make a difference?

BACKGROUND: Inadequate nutrition leading to growth failure is common among premature infants. Although fortified breast milk (breast milk plus commercially prepared fortifier) is the preferred feeding, nutrient intakes achieved with fortified breast milk fall short of meeting nutrient needs. This is mainly due to inadequate protein content of fortifiers and variability in composition of expressed breast milk. OBJECTIVE: A new adjustable fortification regimen has been designed to ensure that protein needs of premature infants are met at all times. The new regimen encompasses increasing the amount of fortifier and adding extra protein to breast milk guided by periodic determinations of blood urea nitrogen (BUN). The study tested the hypothesis that infants fed according to the new regimen have higher protein intakes and improved weight gain compared to infants fed according to standard fortification regimen. METHODS: In a prospective, controlled trial, preterm infants with birth weights of 600-1750 g and gestational ages between 26 and 34 weeks were fed their own mother's milk or banked donor milk or both. Infants were randomly assigned before 21 days of age to either the new adjustable fortification regimen or the standard regimen. The study period began when feeding volume reached 150 ml/kg/day and ended when infants reached a weight of 2000 g. Standard fortification (STD) consisted in the use of the recommended amount of fortifier. Adjustable fortification (ADJ) consisted in the use, in addition to standard fortification, of extra fortifier and supplemental protein guided by twice-weekly BUN determinations. The primary outcome was weight gain, with serum biochemical indicators and nutrient intakes as secondary outcomes. RESULTS: Thirty-two infants completed the study as planned (16 ADJ, 16 STD). Infants receiving the ADJ regimen had mean protein intakes of 2.9, 3.2 and 3.4 g/kg/day, respectively, in weeks 1, 2 and 3, whereas infants receiving the STD regimen had intakes of 2.9, 2.9, 2.8 g/kg/day, respectively. Infants on the ADJ regimen showed significantly greater gain in weight (17.5+/-3.0 vs 14.4+/-3.0 g/kg/day, P<0.01) and greater gain in head circumference (1.4+/-0.3 vs 1.0+/-0.3; P<0.05) than infants on the STD regimen. Weight and head circumference gain were significantly (P<0.05) correlated with protein intake. No significant correlations were found between growth parameters and intake of fat and energy. There were no significant differences between groups in BUN and other serum chemical values. In the ADJ group, BUN concentrations increased significantly (P<0.001) over time but were not significantly higher than in the STD group. CONCLUSION: Premature infants managed with the new adjustable fortification regimen had significantly higher weight and head circumference gains than infants managed with standard fortification. Higher protein intake appears to have been primarily responsible for the improved growth with the adjustable regimen. The new fortification method could be a solution to the problem of protein undernutrition among premature infants fed human milk.

What is the safe protein-energy ratio for infant formulas?

Infants eat primarily to satisfy energy needs and the safe amount of protein in infant formulas (ie, the amount adequate for nearly all infants) is therefore expressed as the protein-energy ratio. We studied male infants aged 8-112 d fed milk-based formulas. One group (experimental group) was fed formulas that provided protein-energy ratios of 3.73 g/MJ (1.56 g/100 kcal) from 8 to 27 d of age, gradually decreasing to 2.99 g/MJ (1.25 g/100 kcal) from 84 to 111 d of age. Growth rates and serum albumin and urea nitrogen of these infants were compared with those of a concurrently studied control group and a previously studied large reference group. Gains in weight and concentrations of serum albumin of the three groups were not significantly different. Gains in length were significantly less for the experimental group than for the reference group. Serum urea nitrogen was significantly less in the experimental group than in the control group or reference group. We conclude that the protein-energy ratios of the experimental formula diet were below the safe level. Because the decrease in growth rate of the experimental group was rather small (demonstrable only in comparison with the large reference group), and because serum albumin of the experimental group increased with age as in normally nourished infants, we suspect that the safe protein-energy ratio of infant formulas lies closer to the ratios fed to the experimental group than to the ratio [approximately 5.0 g/MJ (2.1 g/100 kcal)] in currently marketed milk-based formulas.

Palm olein in infant formula: absorption of fat and minerals by normal infants.

Palm olein, a low-melting fraction of palm oil, and soy oil can be combined to obtain fat blends with proportions of palmitic and oleic acids similar to those of human milk. We compared the absorption of fat and calcium by infants fed a formula containing a blend of palm olein (53%) and soy oil (47%) (Formula PO/S) with that by infants fed a formula containing a blend of soy oil (60%) and coconut oil (40%) (Formula S/C). In a randomized crossover design, one study was performed with each formula in each of 11 normal infants ranging in age from 27 to 161 d. Six of the infants were admitted for 72-h metabolic balance studies. In the other five infants, feces (with some admixture of urine) were collected at home for 96 h by using acid-washed cloth diapers. Mean (+/- SD) absorption of fat was 90.6 +/- 1.6% of intake when Formula PO/S was fed and 95.2 +/- 1.1% of intake when Formula S/C was fed; the difference was significant (P < 0.001). The difference in excretion of fat by infants fed the two formulas was explained by the difference in excretion of palmitic acid. Absorption of calcium averaged 39.0 +/- 8.3% of intake with Formula PO/S and 48.4 +/- 10.3% with Formula S/C; the difference was significant (P < 0.01). We conclude that fat is less well absorbed from a mixture of 53% palm olein and 47% soy oil than from a mixture of 60% soy oil and 40% coconut oil, and that absorption of calcium is less from a formula containing palm olein, presumably because of the formation of insoluble calcium soaps of unabsorbed palmitic acid.

Methionine fortification of a soy protein formula fed to infants.

Data from study of nine normal full-term infants fed a soy isolate-based formula unsupplemented with methionine were compared with similar data from study of 10 similar infants fed the same formula supplemented with L-methionine and with data from previous studies of larger groups of infants receiving various other feedings. Food intake, growth, and serum chemical values were studied from 8 through 111 days of age. In addition, nitrogen balance studies were carried out. Statistically significant differences were as follows: lesser weight gain per 100 kcal by infants fed the unsupplemented soy isolate-based formula than by infants fed milk-based or other soy isolate-based formulas; lesser serum concentrations of albumin at age 28 days by infants fed the unsupplemented soy isolate-based formula than by breast-fed infants; greater serum concentrations of urea nitrogen by infants receiving the unsupplemented soy isolate-based formula than by those receiving the same formula supplemented with L-methionine. A number of other differences was noted but were not statistically significant. The results suggest that normal infants fed a formula providing 2.25 /100 kcal of a soy protein isolate not fortified with methionine performed less well during the first 6 weeks of life than did breast-fed infants and infants fed milk-based formulas or other soy isolate-based formulas fortified with methionine. The limiting nutrient appears to have been methionine.

Plasma amino acid concentrations and amino acid ratios in normal adults and adults heterozygous for phenylketonuria ingesting a hamburger and milk shake meal.

Plasma amino acid concentrations were measured and selected amino acid ratios were calculated in 12 normal adults and 12 adults heterozygous for phenylketonuria (PKU) ingesting a hamburger and milk shake meal providing 1 g protein/kg body wt. Plasma concentrations of all amino acids increased significantly over baseline after meal ingestion in both groups, reaching the highest mean values 3-5 h after meal ingestion. Plasma phenylalanine concentrations were significantly higher in heterozygous than in normal subjects both before and at all times after meal ingestion. The absolute increase in plasma phenylalanine concentration over baseline and the area under the plasma phenylalanine concentration-time curve were approximately twice as large in heterozygous as in normal subjects. However, the molar ratio of the plasma phenylalanine concentration to the sum of the plasma concentrations of the other large neutral amino acids did not increase significantly over baseline, but rather decreased.

Nitrogen balance studies with normal children.

A total of 1148 nitrogen balance studies were conducted in 100 boys and 23 girls 1 to 11 years old. Mixed, customary diets supplied between 8.9 and 21.4% of calories from protein. Duration of balance studies ranged from 72 hr in the youngest subjects to 120 hr in older children. Regressions and 95% confidence intervals of nitrogen retention on nitrogen intake are presented. The slope of the regression was significantly greater for children 12 to 18 months old than for children of other age groups. Correlation coefficients between various parameters of nitrogen balance and energy intake are presented. Although variability in results of nitrogen balances within subjects appears to be rather large, a significant difference between subjects was observed.

Effect of sucrose on the metabolic disposition of aspartame.

Twelve normal adult subjects ingested a beverage providing 0.136 mmol aspartame/kg body wt on 2 different days. On 1 study day the beverage provided only aspartame, on the other the beverage provided both aspartame and 3.51 mmol sucrose/kg body wt. The high mean plasma phenylalanine concentrations were similar after administration of aspartame alone (158 +/- 28.9 mumol/L, mean +/- SD) and administration of aspartame plus sucrose (134 +/- 44.1 mumol/L). Evaluation of the area under the plasma concentration-time curve (AUC) for phenylalanine also showed no significant difference between groups (197 +/- 49.1 vs 182 +/- 28.3 mumol.L-1.h for aspartame alone and aspartame plus sucrose, respectively). Similarly, the high mean ratio of phenylalanine to large neutral amino acids (Phe:LNAA) in plasma did not differ significantly (0.265 +/- 0.046 for aspartame alone, 0.275 +/- 0.107 for aspartame plus sucrose). However, there was a small but significant difference between groups for the 4-h AUC values for plasma Phe:LNAA. The simultaneous ingestion of sucrose with aspartame had only minor effects on aspartame's metabolic disposition.

Lack of adverse reactions to iron-fortified formula.

Some physicians are reluctant to recommend feeding of iron-fortified formulas to infants because of a fear of adverse reactions. In crossover studies, parents' records were compared with regard to their infant's behavior (fussiness, cramps, regurgitation, flatus, colic) and stool characteristics during periods when iron-fortified formulas were fed and periods when non-iron-fortified formulas were fed. No statistically significant feeding-related difference was noted except for stool color.

Strategies for the prevention of iron deficiency: iron in infant formulas and baby foods.

Iron deficiency is the most prevalent nutrition deficiency among infants and young children in industrialized as well as developing countries. It is a condition that is preventable through appropriate dietary measures. The infant born at term is endowed with a sizable amount of iron, which allows the infant to be fed a nearly iron-free diet (e.g., breast milk) for 4-6 months without becoming overtly iron deficient. This has led some to conclude that depletion of iron stores in healthy infants is a normal and, hence, innocuous process that usually gives way to gradual repletion of iron stores as dietary diversification leads to greater iron intakes. Preservation of maternal iron stores at the expense of infant iron stores may have offered survival advantages to the human species during evolution. But there is no evidence that depletion of iron stores can offer advantages to infants in industrialized or developing countries. On the contrary, there is ample documentation of shortterm as well as long-term adverse effects from iron deficiency. Prudence therefore dictates that a high priority be assigned to the prevention of iron depletion and deficiency among infants and young children worldwide.

Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence.

Some clinical studies require administration of test compounds in capsules to assure that the compound cannot be distinguished from a placebo. This raises the question of whether the pharmacokinetic responses produced by capsule administration are similar to values obtained when test compounds are ingested in solution. To test this, plasma phenylalanine and aspartate concentrations were compared in ten normal subjects ingesting 3 g aspartame in solution and in capsules in a balanced Latin square design. Peak plasma phenylalanine levels were significantly higher (191 +/- 65.4 v 117 +/- 39.5 mumol/L, mean +/- SD) and were reached significantly earlier (32 +/- 15 v 123 +/- 74 minutes) when aspartame was administered in solution than when it was administered in capsules. The area under the four-hour plasma phenylalanine concentration-time curve was significantly higher (15,340 +/- 4,820 v 8,465 +/- 3,356 mumol/L X min) when aspartame was ingested in solution. Administration in solution also produced a significantly higher ratio of plasma phenylalanine concentration to the sum of the plasma concentrations of the other large neutral amino acids (0.36 +/- 0.12 v 0.23 +/- 0.06). Similarly, peak plasma aspartate concentrations were significantly higher 26.2 +/- 16.3 v 10.4 +/- 5.0 mumol/L) and were reached significantly earlier (30 +/- 14 v 106 +/- 61.3 min) when aspartame was administered in solution. The data indicate different plasma phenylalanine and aspartate pharmacokinetics between solution and capsule administration of aspartame.

Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults.

Aspartame (APM) is a widely used dipeptide sweetener (L-aspartyl-L-phenylalanine methyl ester). It has been suggested that excessive use of APM might elevate plasma aspartate, phenylalanine, and/or methanol concentrations to levels that are potentially harmful. Six normal young adults ingested eight successive servings of unsweetened and APM-sweetened beverage at one-hour intervals in a balanced crossover design. In one part, the beverage was not sweetened. In the other, each serving of beverage provided 600 mg APM, a dose equivalent to the amount provided by 36 oz of APM-sweetened diet beverage. Plasma aspartate concentration was not significantly increased after ingestion of unsweetened or APM-sweetened beverage. Similarly, ingestion of the unsweetened beverage had no significant effect on plasma phenylalanine concentration. However, ingestion of APM-sweetened beverage significantly increased plasma phenylalanine levels 1.41 to 2.35 mumol/dL above baseline 30 minutes after ingestion. Plasma phenylalanine values reached a steady state after administration of four to five servings and did not exceed normal postprandial values at any time. Blood methanol and formate concentrations remained within normal limits. The data indicate ready metabolism of APM when administered at levels that may be ingested by normal individuals who are heavy users of diet beverages.

Repeated ingestion of aspartame-sweetened beverages: further observations in individuals heterozygous for phenylketonuria.

Six adults heterozygous for phenylketonuria (PKU) ingested eight successive servings of unsweetened and aspartame (APM)-sweetened beverage at 1-hour intervals in a randomized, balanced, crossover design. In one part, the eight beverage servings were not sweetened. In the other, each of the eight beverage servings provided 600 mg of APM, a dose equivalent to the amount provided by 36 oz of an APM-sweetened diet beverage. Plasma aspartate concentration was not significantly increased after ingestion of unsweetened or APM-sweetened beverage. Similarly, ingestion of the unsweetened beverage had no significant effect on plasma phenylalanine concentration. However, ingestion of APM-sweetened beverage significantly increased plasma phenylalanine concentrations 2.35 to 4.03 mumol/dL above baseline 30 minutes after ingestion. Plasma phenylalanine values reached a steady-state after administration of five servings of APM-sweetened beverage and were slightly, but significantly higher than usual postprandial values for adults heterozygous for PKU. Similarly, the ratio of the plasma phenylalanine concentration to the sum of the concentration of the large neutral amino acids was significantly higher than usual postprandial values. Blood methanol and formate concentrations remained within normal limits. These data indicate that a fasting adult heterozygous for PKU could consume the equivalent of 24 12-oz servings of APM-sweetened beverage over an 8-hour period and only increase plasma phenylalanine concentration to a modest degree.

Aspartame ingestion with and without carbohydrate in phenylketonuric and normal subjects: effect on plasma concentrations of amino acids, glucose, and insulin.

Seven subjects homozygous for phenylketonuria (PKU) and seven normal subjects were administered four beverage regimens after an overnight fast: unsweetened beverage, beverage providing carbohydrate (CHO), beverage providing aspartame (APM), and beverage providing APM plus CHO. The APM dose (200 mg) was the amount provided in 12 oz of diet beverage; the CHO was partially hydrolyzed starch (60 g). Plasma amino acid concentrations were determined after dosing and the molar plasma phenylalanine (Phe) to large neutral amino acid (LNAA) ratio calculated. APM administration without CHO did not increase plasma Phe concentrations over baseline values in either normal or PKU subjects (5.48 +/- 0.85 and 150 +/- 23.0 mumols/dL, respectively). Similarly, the Phe/LNAA did not increase significantly. Ingestion of beverage providing APM and CHO did not significantly increase plasma Phe concentrations over baseline values in either normal or PKU subjects. However, ingestion of beverage providing CHO (with or without APM) significantly decreased plasma levels of valine, isoleucine, and leucine 1.5 to 4 hours after dosing in both normal and PKU subjects, thereby increasing the Phe/LNAA ratio significantly. These data indicate that changes noted in Phe/LNAA values after ingestion of beverage providing APM plus CHO were due to CHO. The plasma insulin response to beverage providing CHO (with or without APM) was significantly higher in PKU subjects than in normals.

Repeated ingestion of aspartame-sweetened beverage: effect on plasma amino acid concentrations in individuals heterozygous for phenylketonuria.

It has been suggested that excessive use of aspartame (APM) (N-L-alpha-aspartyl-L-phenylalanine methyl ester) might grossly elevate plasma aspartate and phenylalanine concentrations in individuals heterozygous for phenylketonuria (PKUH). In study 1 six adult PKUH (three males; three females) ingested three successive 12-oz servings of beverage at 2-h intervals. The study was carried out in two parts in a randomized crossover design. In one arm the beverage was not sweetened. In the other the beverage provided 10 mg APM/kg body weight per serving. The addition of APM to the beverage did not significantly increase plasma aspartate concentration but did increase plasma phenylalanine levels 2.3 to 4.1 mumol/dL above baseline values 30 to 45 min after each dose. The high mean plasma phenylalanine level after repeated APM dosing (13.9 +/- 2.15 mumol/dL) was slightly, but not significantly, above the normal postprandial range for PKUH (12.6 +/- 2.11 mumol/dL). In study 2 six different adult PKUH ingested beverage providing 30 mg APM/kg body weight as a single bolus. The high mean plasma phenylalanine concentration and the phenylalanine to large neutral amino acid ratio were significantly higher when APM was ingested as a single bolus than when ingested as a divided dose.

Intestinal blood loss during cow milk feeding in older infants: quantitative measurements.

OBJECTIVE: To determine the response, in terms of fecal hemoglobin excretion and clinical symptoms, of normal 9 1/2-month-old infants to being fed cow milk. DESIGN: Longitudinal (before-after) trial in which each infant was fed formula for 1 month (baseline) followed by 3 months during which cow milk was fed. SETTING: Healthy infants living in Iowa City, Iowa, a town with a population of about 60,000. MAIN OUTCOME MEASURES: Hemoglobin concentration in spot stools, 96-hour quantitative fecal hemoglobin excretion, stool characteristics, feeding-related behaviors, and iron nutritional status. RESULTS: Fecal hemoglobin concentration during formula feeding (baseline) was higher than previously observed in younger infants. Nine of 31 infants responded to cow milk feeding with increased fecal hemoglobin concentration. Fecal hemoglobin concentration (mean +/- SD) of the 9 responders rose from 1,395 +/- 856 microg/g of dry stool (baseline) to 2,711 +/- 1,732 microg/g of dry stool (P=.01). The response rate (29%) was similar to that in younger infants, but the intensity of the response was much less. Quantitative hemoglobin excretion was in general agreement with estimates based on spot stool hemoglobin concentrations. Cow milk feeding was not associated with recognizable changes in stool characteristics, nor were there clinical signs related to fecal blood loss. Iron status was similar, except that after 3 months of cow milk feeding responders showed lower (P= .047) ferritin concentrations than nonresponders. CONCLUSIONS: Cow milk-induced blood loss is present in 9 1/2-month-old infants but is of such low intensity that its clinical significance seems questionable. Nevertheless, infants without cow milk-induced blood loss were in better iron nutritional status than infants who showed blood loss.

Riboflavin enhances photo-oxidation of amino acids under simulated clinical conditions.

In neonatal nurseries, solutions of amino acids with added vitamins may be exposed to relatively intense light from phototherapy units. Light, especially in the presence of photosensitizers such as certain vitamins, is capable of destroying amino acids. In the present study, the effect of riboflavin on amino acid concentrations in solutions exposed to light was studied. Solutions of crystalline amino acids with and without added riboflavin were infused into shielded collecting vessels for 24 hr under conditions simulating those occurring during phototherapy. Decreases in concentrations of some amino acids were observed with light exposure alone. Decreases in concentrations of methionine, proline, tryptophan, and tyrosine were significantly greater in the presence of riboflavin that in its absence. Riboflavin concentrations were also significantly reduced after light exposure. Although the losses of amino acids are probably not nutritionally significant, the photo-oxidation products are largely unknown and may be toxic.

Retinol-binding protein and prealbumin in cord blood of term and preterm infants.

Retinol-binding protein (RBP) and prealbumin (PA) are potentially useful indicators of inadequate protein and/or energy intake. Concentrations of RBP and PA were determined in cord blood of 117 infants and were found to be lower before 37 weeks gestation than at term. Adult subjects had substantially higher concentrations of RBP and PA than found in cord blood.

Gain in weight and length during early infancy.

Although rate of growth is generally recognized as a valuable indicator of health status, few reference data are available for gain in weight or length during the period of most growth in infancy. We have therefore summarized our data concerning gains in length and weight of 203 breast-fed males, 216 breast-fed females, 380 formula-fed males, and 340 formula-fed females. Seven sets of measurements (at ages 8, 14, 28, 42, 56, 84 and 112 days) were made with each infant. The 5th, 10th, 25th, 50th, 75th, 90th and 95th centile values together with the means and standard deviations are presented for selected age intervals on a feeding-specific (i.e. breast-fed or formula-fed) and sex-specific basis. We believe that these data will be useful as a reference for interpreting results of infant studies.

Nutrient intakes and growth of very low birth weight infants.

OBJECTIVE: Our purpose was to determine nutrient intakes and growth of very low birth weight (VLBW) infants. STUDY DESIGN: The survey consisted of infants admitted during a 9-month period to a tertiary neonatal center. Data were obtained concerning all 51 infants born weighing <1300 gm who survived beyond 21 days of age. METHODS: At weekly intervals, intakes of fluid, energy, and protein from all sources were determined and body weight was recorded. RESULTS: During the first 2 weeks of life, intake of energy (predominantly parenteral) averaged 75 +/- 12 kcal/kg per day and intake of protein averaged 1.9 +/- 0.5 gm/kg per day. From 15 to 35 days, intake of energy (transition from parenteral to enteral) averaged 99 +/- 12 kcal/kg per day and intake of protein averaged 2.5 gm/kg per day. During the period 36 to 56 days (early enteral) and 57 days to term (late enteral), energy intakes were 108 +/- 13 and 110 +/- 15 kcal/kg per day, respectively, and protein intakes were 2.7 +/- 0.5 and 2.7 +/- 0.5 gm/kg per day, respectively. These low intakes of energy and protein (relative to presumed requirements) were explained by low intake volumes and low protein concentrations of feedings. Weight reached birth weight by 14 days of age. Subsequently, weight gains averaged 13.0, 13.8, and 11.6 gm/kg per day, respectively, in successive periods. These gains were lower than would have occurred in utero. CONCLUSION: Observed growth of VLBW infants was slow relative to in utero growth, presumably because intakes of energy and, in particular, of protein fell short of intakes needed to duplicate in utero growth. Changes in feeding practices, as well as in composition of feedings, are needed if in utero growth is to be matched.