Harrie N. Lafeber

Optimal growth and lower fat mass in preterm infants fed a protein-enriched postdischarge formula.

Background and Objectives: Postdischarge formulas with extra energy and protein improve short-term growth but may also influence long-term body composition in an unwanted manner. Energy- and protein-enriched formulas with an increased protein-to-energy ratio improves gain of lean mass. The objective of the study was to investigate whether feeding a nutrient-enriched formula without extra energy after term, usually 3 to 4 weeks after discharge, would influence growth and body composition in infancy. Methods: In this randomized controlled trial preterm infants were fed fortified human milk or preterm formula until term. At term, 102 infants were randomized to a nutrient-enriched formula without extra energy or standard formula until 6 months corrected age. Twenty-six infants received unfortified human milk after term. At term and 6 months corrected age, anthropometry and a dual-energy x-ray absorptiometry (DEXA) scan were performed. Lean and fat mass (FM) were corrected for height. Results: There were no differences in growth or body size between the feeding groups. Infants fed the enriched formula gained less FM and had lower FM corrected for body size at 6 months corrected age than infants fed standard formula. Infants fed human milk had lower lean mass and higher FM corrected for body size at 6 months corrected age than formula-fed infants. Conclusions: Feeding nutrient-enriched formula without extra energy after term does not change quantity of growth but does influence type of weight gain and body composition of preterm infants. Infants fed the nutrient-enriched formula had lower FM corrected for body size at 6 months corrected age than infants fed standard formula or human milk.

Neutral and acidic oligosaccharides in preterm infants: a randomized, double-blind, placebo-controlled trial

BACKGROUND Serious infectious morbidity is high in preterm infants. Enteral supplementation of prebiotics may reduce the incidence of serious infections, especially infections related to the gastrointestinal tract. OBJECTIVE The objective was to determine the effect of enteral supplementation of a prebiotic mixture consisting of neutral oligosaccharides ((SC)GOS/(LC)FOS) and acidic oligosaccharides (AOS) on serious infectious morbidity in preterm infants. DESIGN In a randomized controlled trial, preterm infants (gestational age <32 wk and/or birth weight <1500 g) received enteral supplementation of 80% (SC)GOS/(LC)FOS and 20% AOS (1.5 g . kg(-1) . d(-1)) or placebo (maltodextrin) between days 3 and 30 of life. Serious infectious morbidity was defined as a culture positive for sepsis, meningitis, pyelonephritis, or pneumonia. The analysis was performed by intention-to-treat and per-protocol, defined as > or =50% supplementation dose during the study period. RESULTS In total, 113 preterm infants were included. Baseline and nutritional characteristics were not different between groups. In the intention-to-treat analysis, the incidence of > or =1 serious infection, > or =1 serious endogenous infection, or > or =2 serious infectious episodes was not significantly different in the (SC)GOS/(LC)FOS/AOS-supplemented and placebo groups. In the per-protocol analysis, there was a trend toward a lower incidence of > or =1 serious endogenous infection and > or =2 serious infectious episodes in the (SC)GOS/(LC)FOS/AOS-supplemented group than in the placebo group (P = 0.09 and P = 0.07, respectively). CONCLUSIONS Enteral supplementation of (SC)GOS/(LC)FOS/AOS does not significantly reduce the risk of serious infectious morbidity in preterm infants. However, there was a trend toward a lower incidence of serious infectious morbidity, especially for infections with endogenous bacteria. This finding suggests a possible beneficial effect that should be evaluated in a larger study. This trial was registered at isrctn.org as ISRCTN16211826.

Arginine and Mixed Amino Acids Increase Protein Accretion in the Growth-Restricted and Normal Ovine Fetus by Different Mechanisms

Protein metabolism may be perturbed in intrauterine growth restriction (IUGR). Arginine is indispensable for growth and nitrogen balance in young mammals. Fetuses with IUGR therefore may benefit from arginine supplementation. The purpose of this study was to determine 1) the effects of IUGR on protein metabolism in the ovine fetus and 2) the effects of arginine or mixed amino acid (AA) infusion on protein metabolism in these fetuses. Pregnant ewes and their fetuses were catheterized at 110 d gestation and randomly assigned to control or IUGR groups. IUGR was induced by repetitive placental embolization. Parameters of fetal protein metabolism were determined from [ring-2H5]phenylalanine kinetics at baseline and in response to a 4-h infusion of either arginine or an isonitrogenous AA mixture. There were no differences in protein metabolism between control and IUGR groups either at baseline or in response to arginine or AA treatment. Both arginine and AA infusion increased fetal protein accretion in both groups. Arginine did this by decreasing protein turnover, synthesis, and breakdown. AAs increased protein turnover and synthesis while decreasing protein breakdown. AA infusion resulted in a significantly higher increase in protein accretion than arginine infusion. Thus, in the ovine fetus, placental embolization has no clear effect on protein metabolism. Arginine and AAs both stimulate protein accretion but do so in distinctly different ways. Mixed AA infusion has a greater effect on protein accretion than arginine alone and therefore may be a better strategy for stimulating fetal growth.

The effect of enteral supplementation of a prebiotic mixture of non-human milk galacto-, fructo- and acidic oligosaccharides on intestinal permeability in preterm infants.

Preterm infants have an impaired gut barrier function. We aimed to determine the effects of enteral supplementation of a prebiotic mixture consisting of neutral oligosaccharides (short-chain galacto-oligosaccharides (SCGOS)/long-chain fructo-oligosaccharides (LCFOS)) and acidic oligosaccharides (AOS) on intestinal permeability of preterm infants as measured by the sugar absorption test in the first week of life. Furthermore, we determined host- and treatment-related factors associated with intestinal permeability. In a randomised controlled trial, preterm infants with a gestational age < 32 weeks and/or birth weight (BW) < 1500 g received enteral supplementation of SCGOS/LCFOS/AOS or placebo (maltodextrin) between days 3 and 30 of life. Intestinal permeability, reflected by the urinary lactulose/mannitol (L/M) ratio after oral ingestion of lactulose and mannitol, was assessed at three time points: before the start of the study (t = 0), at day 4 (t = 1) and at day 7 (t = 2) of life. Data were analysed by generalised estimating equations. In total, 113 infants were included. Baseline patient and nutritional characteristics were not different between the SCGOS/LCFOS/AOS (n 55) and the placebo groups (n 58). SCGOS/LCFOS/AOS had no effect on the L/M ratio between t = 0 and t = 2. In both the groups, the L/M ratio decreased from t = 0 to t = 2 (P < 0·001). Low BW increased the L/M ratio (P = 0·002). Exclusive breast milk feeding and mixed breast milk/formula feeding during the first week of life decreased the L/M ratio (P < 0·001 and P < 0·05, respectively). In conclusion, enteral supplementation of a prebiotic mixture does not enhance the postnatal decrease in intestinal permeability in preterm infants in the first week of life.

Design of a randomised controlled trial on immune effects of acidic and neutral oligosaccharides in the nutrition of preterm infants: carrot study

BackgroundPrevention of serious infections in preterm infants is a challenge, since prematurity and low birth weight often requires many interventions and high utility of devices. Furthermore, the possibility to administer enteral nutrition is limited due to immaturity of the gastrointestinal tract in the presence of a developing immune system. In combination with delayed intestinal bacterial colonisation compared with term infants, this may increase the risk for serious infections. Acidic and neutral oligosaccharides play an important role in the development of the immune system, intestinal bacterial colonisation and functional integrity of the gut. This trial aims to determine the effect of enteral supplementation of acidic and neutral oligosaccharides on infectious morbidity (primary outcome), immune response to immunizations, feeding tolerance and short-term and long-term outcome in preterm infants. In addition, an attempt is made to elucidate the role of acidic and neutral oligosaccharides in postnatal modulation of the immune response and postnatal adaptation of the gut.Methods/DesignIn a double-blind placebo controlled randomised trial, 120 preterm infants (gestational age <32 weeks and/or birth weight <1500 gram) are randomly allocated to receive enteral acidic and neutral oligosaccharides supplementation (20%/80%) or placebo supplementation (maltodextrin) between day 3 and 30 of life. Primary outcome is infectious morbidity (defined as the incidence of serious infections). The role of acidic and neutral oligosaccharides in modulation of the immune response is investigated by determining the immune response to DTaP-IPV-Hib(-HBV)+PCV7 immunizations, plasma cytokine concentrations, faecal Calprotectin and IL-8. The effect of enteral acidic and neutral oligosaccharides supplementation on postnatal adaptation of the gut is investigated by measuring feeding tolerance, intestinal permeability, intestinal viscosity, and determining intestinal microflora. Furthermore, short-term and long-term outcome are evaluated.DiscussionEspecially preterm infants, who are at increased risk for serious infections, may benefit from supplementation of prebiotics. Most studies with prebiotics only focus on the colonisation of the intestinal microflora. However, the pathways how prebiotics may influence the immune system are not yet fully understood. Studying the immune modulatory effects is complex because of the multicausal risk of infections in preterm infants. The combination of neutral oligosaccharides with acidic oligosaccharides may have an increased beneficial effect on the immune system. Increased insight in the effects of prebiotics on the developing immune system may help to decrease the (infectious) morbidity and mortality in preterm infants.Trial registrationCurrent Controlled Trials ISRCTN16211826.

The effect of neutral and acidic oligosaccharides on stool viscosity, stool frequency and stool pH in preterm infants

Aim:  To determine the effect of neutral oligosaccharides [small‐chain galacto‐oligosaccharides/long‐chain fructo‐oligosaccharides (scGOS/lcFOS)] in combination with acidic oligosaccharides (pAOS) on stool viscosity, stool frequency and stool pH in preterm infants.

Accuracy of oscillometric blood pressure measurement in critically ill neonates with reference to the arterial pressure wave shape

ObjectiveTo perform further evaluation of the oscillometric device for neonatal arterial blood pressure (ABP) measurement, using a catheter-manometer system (CMS) for accurate intraarterial measurement. We aimed to describe the influence of the radial artery wave shape on oscillometric ABP determination, as pressure, wave-shape influences the relationships between systolic arterial pressure (SAP),diastolic arterial pressure (DAP) and mean arterial pressure (MAP) in the wave. These relationships are part of the algorithms contributing to the final ABP determination in the oscillometric device.DesignIntra-patient comparison of two blood pressure measurement systems.SettingNeonatal intensive care unit.PatientsIn 51 critically ill newborn infants, ABP was determined oscillometrically in the brachial artery and, simultaneously, invasively in the radial artery using a high-fidelity CMS. Clinical data of the infants were: gestational age: 29 (25–41) weeks; brithweight: 1200 (500–3675) g, postnatal age: 6 (2–46) h.MethodsStatistical analysis was performed with the paired Studentst-test. Multiple regression analysis was used to determine the influence of birthweight and height of the blood pressure on the results.Measurements and main resultsIn 51 infants, 255 paired values of SAP, DAP and MAP were recorded. In all recordings we determined the relationship between SAP, DAP and MAP, using the equation.MAP=α%(SAP-DAP)+DAP. For SAP, DAP, MAP and α, we computed mean differences (bias) and the limits of agreement (precision). Biases for SAP, DAP, MAP and α were significantly different from zero (P<0.001) and the limits of agreement for SAP, DAP and MAP were wide: 18.8 mmHg, 17.2 mmHg and 15.2 mmHg respectively The relationship between invasive and noninvasive values is only partly (7–19%) influenced by the height of the blood pressure; low values of SAP, DAP and MAP tend to give overestimated oscillometric values. In the relationship between SAP, DAP and MAP, α was found to be 47% invasively (as generally found in the radial artery in newborns) and 34% noninvasively (as generally found in the brachial/radial artery in adults).ConclusionsInaccuracy of the oscillometric device may be partly explained by the incorporation of an inappropriately fixed algorithm for final ABP determination in newborns. Care should be taken when interpreting the oscillometrically derived values in critically ill newborn infants.

Majority of dietary glutamine is utilized in first pass in preterm infants

Glutamine is a conditionally essential amino acid for very low-birth weight infants by virtue of its ability to play an important role in several key metabolic processes of immune cells and enterocytes. Although glutamine is known to be used to a great extend, the exact splanchnic metabolism in enterally fed preterm infants is unknown. We hypothesized that preterm infants show a high splanchnic first-pass glutamine metabolism and the primary metabolic fate of glutamine is oxidation. Five preterm infants (mean ± SD birth weight 1.07 ± 0.22 kg and GA 29 ± 2 wk) were studied by dual tracer ([U-13C]glutamine and [15N2]glutamine) cross-over techniques on two study days (at postnatal week 3 ± 1 wk). Splanchnic and whole-body glutamine kinetics were assessed by plasma isotopic enrichment of [U-13C]glutamine and [15N2]glutamine and breath 13CO2 enrichments. Mean fractional first-pass glutamine uptake was 73 ± 6% and 57 ± 17% on the study days. The splanchnic tissues contributed for a large part (57 ± 6%) to the total amount of labeled carbon from glutamine retrieved in expiratory air. Dietary glutamine is used to a great extent by the splanchnic tissues in preterm infants and its carbon skeleton has an important role as fuel source.

A Randomized Controlled Trial of Enteral Glutamine Supplementation in Very Low Birth Weight Infants: Plasma Amino Acid Concentrations

Objective: Glutamine depletion has negative effects on the functional integrity of the gut and leads to immunosuppression. Very low birth weight (VLBW) infants are susceptible to glutamine depletion, as enteral nutrition is limited in the first weeks of life. Enteral glutamine supplementation may have a positive effect on feeding tolerance, infectious morbidity and short-term outcome. The aim of the study was to determine the effect of enteral glutamine supplementation on plasma amino acid concentrations, reflecting one aspect of safety of enteral glutamine supplementation in VLBW infants. Methods: In a double-blind placebo-controlled randomized controlled trial, VLBW infants (gestational age <32 weeks or birth weight <1500 g) received enteral glutamine supplementation (0.3 g/kg per day) or isonitrogenous placebo supplementation (alanine) between day 3 and day 30 of life. Supplementation was added to breast milk or to preterm formula. Plasma amino acid concentrations were measured at four time points: before the start of the study and at days 7, 14 and 30 of life. Results: Baseline patient and nutritional characteristics were not different in glutamine (n = 52) and control (n = 50) groups. Plasma concentrations of most essential and non-essential amino acids increased throughout the study period. There was no effect of enteral glutamine supplementation. In particular, the increase of plasma glutamine and glutamate concentrations was not different between the treatment groups (P = 0.49 and P = 0.34 respectively, day 30). Conclusions: Enteral glutamine supplementation in VLBW infants does not alter plasma concentrations of glutamine, glutamate or other amino acids. Enteral supplementation in a dose of 0.3 g/kg per day seems safe in VLBW infants.

Timing of nutritional interventions in very-low-birth-weight infants: optimal neurodevelopment compared with the onset of the metabolic syndrome

Recent nutritional research in very-low-birth-weight (VLBW) infants is focused on the prevention of protein malnutrition during the first postnatal weeks. At this early age, nutritional protein fortification depends on amino acid infusion via a central vein because of the immature gastrointestinal tract. In 2010 new guidelines on nutrition were proposed by the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition nutrition committee. In particular, the relative increase in the protein fraction in the nutrition of these infants aims to prevent early postnatal weight loss, to prevent morbidity, and to stimulate neurodevelopment. On the other hand, an increasing number of follow-up studies in VLBW infants indicate that, in particular, those infants who show rapid growth after preterm birth are at risk of metabolic consequences and cardiovascular disease later in life. In this review, we describe the quest to develop a customized diet that offers optimal nutrition at several time points of growth and development during the first year of life. This diet should prevent early malnutrition, enhance neurodevelopment, and limit the increase in total body fat during the first 6 mo. We question whether one type of early diet suffices for normal neurodevelopment with a normal body composition in later life or whether we need several types of diet at various stages of development.