Sissel J. Moltu

Enhanced Feeding and Diminished Postnatal Growth Failure in Very-Low-Birth-Weight Infants

Objective: The aim of the present study was to determine whether an increased supply of energy, protein, essential fatty acids, and vitamin A reduces postnatal growth failure in very-low-birth-weight infants. Methods: Fifty infants with birth weight <1500 g were randomized to an intervention (n = 24) or a control (n = 26) feeding protocol within 24 hours after birth. Forty-four infants were included in the final analysis. This study was discontinued because of an increased occurrence of septicemia in the intervention group. Results: The intervention group had a lower mean birth weight (P = 0.03) and a higher proportion of infants small-for-gestational age (P = 0.04) than the control group. Other baseline characteristics were similar. The median (interquartile range) energy and protein supplies during the first 4 weeks of life were higher in the intervention group: 139 (128–145) versus 126 (121–128) kcal · kg−1 · day−1 (P < 0.001) and 4.0 (3.9–4.2) versus 3.2 (3.1–3.3) g · kg−1 · day−1 (P < 0.001). The infants in the intervention group regained birth weight faster (P = 0.001) and maintained their z scores for weight and head circumference from birth to 36 weeks’ postmenstrual age (both P < 0.001). The median (interquartile range) growth velocity was 17.4 (16.3–18.6) g · kg−1 · day−1 in the intervention group and 13.8 (13.2–15.5) g · kg−1 · day−1 in the control group (P < 0.001). In line with the improved growth in the intervention group, the proportion of growth-restricted infants was 11 of 23 both at birth and at 36 weeks’ postmenstrual age, whereas this proportion increased among the controls from 4 of 21 to 13 of 21 (P = 0.04). Conclusions: Enhanced supply of energy, protein, essential fatty acids, and vitamin A caused postnatal growth along the birth percentiles for both weight and head circumference.

Urinary Metabolite Profiles in Premature Infants Show Early Postnatal Metabolic Adaptation and Maturation

Objectives: Early nutrition influences metabolic programming and long-term health. We explored the urinary metabolite profiles of 48 premature infants (birth weight < 1500 g) randomized to an enhanced or a standard diet during neonatal hospitalization. Methods: Metabolomics using nuclear magnetic resonance spectroscopy (NMR) was conducted on urine samples obtained during the first week of life and thereafter fortnightly. Results: The intervention group received significantly higher amounts of energy, protein, lipids, vitamin A, arachidonic acid and docosahexaenoic acid as compared to the control group. Enhanced nutrition did not appear to affect the urine profiles to an extent exceeding individual variation. However, in all infants the glucogenic amino acids glycine, threonine, hydroxyproline and tyrosine increased substantially during the early postnatal period, along with metabolites of the tricarboxylic acid cycle (succinate, oxoglutarate, fumarate and citrate). The metabolite changes correlated with postmenstrual age. Moreover, we observed elevated threonine and glycine levels in first-week urine samples of the small for gestational age (SGA; birth weight < 10th percentile for gestational age) as compared to the appropriate for gestational age infants. Conclusion: This first nutri-metabolomics study in premature infants demonstrates that the physiological adaptation during the fetal-postnatal transition as well as maturation influences metabolism during the breastfeeding period. Elevated glycine and threonine levels were found in the first week urine samples of the SGA infants and emerged as potential biomarkers of an altered metabolic phenotype.

Enhanced Nutrient Supply to Very Low Birth Weight Infants is Associated with Improved White Matter Maturation and Head Growth

Background: Extrauterine growth restriction is common among very low birth weight infants (VLBW, BW <1,500 g). Optimal postnatal nutrient supply is essential to limit growth restriction and ensure adequate growth and neurodevelopment. Objectives: We compared an enhanced postnatal nutrient supply to a standard supply and evaluated the effects on growth velocity, head circumference growth and cerebral maturation - the latter by magnetic resonance diffusion tensor imaging (DTI). We hypothesized increased growth velocity, head circumference growth and decreased mean diffusivity (MD) in cerebral white matter (WM) areas, suggesting improved cerebral maturation among infants on the enhanced nutrient supply. Methods: In this randomized controlled trial, infants on the enhanced nutrient supply received increased amounts of energy, protein, fat, essential fatty acids and vitamin A until discharge. DTI was performed close to term equivalent age. Outcomes were growth velocity, head circumference growth and WM mean diffusivity. Results: Among the 50 included infants, 14 in the intervention group and 11 controls underwent a successful DTI. Infants on the enhanced diet achieved improved growth velocity (16.5 vs. 13.8 g/kg/day, p = 0.01) and increased head circumference (Δz score: 0.24 vs. -0.12, p = 0.15). A significantly lower MD was seen in a large WM area such as the superior longitudinal fasciculi (1.19 × 10-3 vs. 1.24 × 10-3 mm2/s, p = 0.04, adjusted for age when scanned). Conclusions: Enhanced nutrient supply to VLBW infants is associated with improved growth velocity, increased head circumference growth and decreased regional WM mean diffusivity, suggesting improved maturation of cerebral connective tracts.

Long-Chain Polyunsaturated Fatty Acids and Clinical Outcomes of Preterm Infants.

Long-chain polyunsaturated fatty acids (LCPUFAs) play specific roles during the perinatal period and are very important nutrients to consider. The possible effects of LCPUFAs, particularly docosahexaenoic acid (DHA), on various clinical outcomes of preterm infants are discussed in this paper. Since DHA accumulates in the central nervous system during development, a lot of attention has focused on the effects of DHA on neurodevelopment. Experimental studies as well as recent clinical trials show that providing larger amounts of DHA than currently and routinely provided is associated with better neurological outcomes at 18 months to 2 years. This early advantage, however, does not seem to translate into detectable change in visual and neurodevelopmental outcomes or behavior when assessed in childhood. There is growing evidence that, in addition to effects on development, omega-3 LCPUFAs may reduce the incidence or severity of neonatal morbidities by affecting different steps of the immune and anti-inflammatory response. Studies in preterm infants suggest that the omega-3 LCPUFAs may play a significant role by reducing the risk of bronchopulmonary dysplasia, necrotizing enterocolitis and possibly retinopathy of prematurity and sepsis. Overall, evidence is increasing to support the benefits of high-dose DHA for various health outcomes of preterm infants. These findings are of major clinical relevance mainly because infants born preterm are at particularly high risk for a nutritional deficit in omega-3 fatty acids, predisposing to adverse neonatal outcomes. Further studies are warranted to address these issues as well as to more precisely determine the LCPUFA requirement in order to favor the best possible outcomes of preterm infants.

Intestinal microbiota development and gestational age in preterm neonates

The intestinal microbiota is an important contributor to the health of preterm infants, and may be destabilized by a number of environmental factors and treatment modalities. How to promote the development of a healthy microbiota in preterm infants is largely unknown. We collected fecal samples from 45 breastfed preterm very low birth weight (birth weight < 1500 g) infants from birth until 60 days postnatal age to characterize the intestinal microbiota development during the first weeks of life in preterm infants. Fecal microbiota composition was determined by 16S rRNA amplicon sequencing. The main driver of microbiota development was gestational age; antibiotic use had strong but temporary effects and birth mode had little influence. Microbiota development proceeded in four phases indicated by the dominance of Staphylococcus, Enterococcus, Enterobacter, and finally Bifidobacterium. The Enterococcus phase was only observed among the extremely premature infants and appeared to delay the microbiota succession. The results indicate that hospitalized preterm infants receiving breast milk may develop a normal microbiota resembling that of term infants.

Serum Magnesium Levels in Preterm Infants Are Higher Than Adult Levels: A Systematic Literature Review and Meta-Analysis

Magnesium (Mg) is an essential mineral in the body, impacting the synthesis of biomacromolecules, bone matrix development, energy production, as well as heart, nerve, and muscle function. Although the importance of Mg is evident, reference values for serum Mg (sMg) in pediatric patients (more specifically, in neonates) are not well established. This systematic literature review and meta-analysis (using 47 eligible studies) aims to quantify normal and tolerable ranges of sMg concentrations during the neonatal period and to highlight the factors influencing Mg levels and the importance of regulating sMg levels during pregnancy and birth. In newborns without Mg supplementation during pregnancy, magnesium levels at birth (0.76 (95% CI: 0.52, 0.99) mmol/L) were similar to that of mothers during pregnancy (0.74 (95% CI: 0.43, 1.04) mmol/L), but increased during the first week of life (0.91 (95% CI: 0.55, 1.26) mmol/L) before returning to adult levels. This pattern was also seen in newborns with Mg supplementation during pregnancy, where the average was 1.29 (95% CI: 0.50, 2.08) mmol/L at birth and 1.44 (95% CI: 0.61, 2.27) mmol/L during the first week of life. Factors influencing these levels include prenatal Mg supplementation, gestational age, birth weight, renal maturity/function, and postnatal Mg intake. Elevated Mg levels (>2.5 mmol/L) have been associated with an increased risk of mortality, admission into intensive care, hypotonia, hypotension, and respiratory depression but sMg concentrations up to 2.0 mmol/L appear to be well tolerated in neonates, requiring adequate survey and minimal intervention.

Increased levels of phthalates in very low birth weight infants with septicemia and bronchopulmonary dysplasia.

Very low birth weight infants (VLBW; birth weight<1500g) are exposed to potentially harmful phthalates from medical devices during their hospital stay. We measured urinary phthalate concentrations among hospitalized VLBW infants participating in a nutritional study. Possible associations between different phthalates and birth weight (BW), septicemia and bronchopulmonary dysplasia (BPD) were evaluated. Forty-six VLBW infants were enrolled in this randomized controlled nutritional study. The intervention group (n=24) received increased quantities of energy, protein, fat, essential fatty acids and vitamin A, as compared to the control group (n=22). The concentrations of 12 urinary phthalate metabolites were measured, using high-performance liquid chromatography coupled to tandem mass spectrometry, at 3 time points during the first 5weeks of life. During this study, the levels of di (2-ethylhexyl) phthalate (DEHP) metabolites decreased, whereas an increasing trend was seen regarding metabolites of di-iso-nonyl phthalate (DiNP). Significantly higher levels of phthalate metabolites were seen in infants with lower BW and those diagnosed with late onset septicemia or BPD. A significant positive correlation between the duration of respiratory support and DEHP metabolites was observed (p≤0.01) at 2.9weeks of age. Birth weight was negatively associated with urinary phthalate metabolite concentrations. Infants with lower BW and those diagnosed with septicemia or BPD experienced prolonged exposure from medical equipment containing phthalates, with subsequent higher levels of phthalate metabolites detected. Clinical Trial Registration no.: NCT01103219.

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

Background: Previous guidelines on Paediatric Parenteral Nutrition (PN) were published in 2010, by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR) were published. The aim of the present paper was to provide up-to-date evidence for health professionals working with infants, children and adolescents receiving PN. Methods: The current document is a revision of the 2005 guidelines produced by the same 3 organizations (ESPEN, ESPGHAN, ESPR) together with the Chinese Society of Parenteral and Enteral Nutrition (CSPEN). Experts participating in the guideline updating process were all professionals with extensive experience in managing PN from a wide range of European countries, Israel and China. The guideline development process was coordinated by a guideline steering committee. Each chapter of the guideline was prepared by a separate author group. These author groups were responsible for screening titles and abstracts identified by a systematic literature search for inclusion, for conducting additional expert searches (including secondary sources such as other published valid guidelines), for evaluating the quality of studies included in the given chapter and assigning evidence levels to the literature. Based on the evidence level of included studies experts formulated and graded recommendations. A consensus conference was held in February 2015. All chapter manuscripts were revised following the recommendations of the consensus conference and then reviewed and edited by the project steering committee. Final consensus on each individual guideline and its individual recommendations was achieved and assessed by online voting. This process lasted until January 2018. Funding for the consensus conference (including travel expenses for participants) was provided by all participating societies. No other funding was received for the guideline updating process and participants received no payment. Support was provided by the Hungarian Cochrane organization. Results/conclusions: The present document provides guideline for the use of PN across the wide range of pediatric patients, ranging from extremely premature infants up to teenagers weighing up to and over 100 kg [1]. It covers their individual macro- and micronutrient needs [2], [3], [4], [5], [6], [7], [8], fluid requirements [9], venous access [10], organizational aspects [11], home parenteral nutrition [12], standardized vs. individualized PN [13], and last but not least a wide range of safety considerations for prevention and management of complications such central line associated bloodstream infections (CLABSI) [14].

Enhanced nutrition improves growth and increases blood adiponectin concentrations in very low birth weight infants

Background Adequate nutrient supply is essential for optimal postnatal growth in very low birth weight (VLBW, birth weight<1,500 g) infants. Early growth may influence the risk of metabolic syndrome later in life. Objective To evaluate growth and blood metabolic markers (adiponectin, leptin, and insulin-like growth factor-1 (IGF-1)) in VLBW infants participating in a randomized nutritional intervention study. Design Fifty VLBW infants were randomized to an enhanced nutrient supply or a standard nutrient supply. Thirty-seven infants were evaluated with growth measurements until 2 years corrected age (CA). Metabolic markers were measured at birth and 5 months CA. Results Weight gain and head growth were different in the two groups from birth to 2 years CA (weight gain: pinteraction=0.006; head growth: pinteraction=0.002). The intervention group improved their growth z-scores after birth, whereas the control group had a pronounced decline, followed by an increase and caught up with the intervention group after discharge. At 5 months CA, adiponectin concentrations were higher in the intervention group and correlated with weight gain before term (r=0.35) and nutrient supply (0.35≤r≤0.45). Leptin concentrations correlated with weight gain after term and IGF-1 concentrations with length growth before and after term and head growth after term (0.36≤r≤0.53). Conclusion Enhanced nutrient supply improved early postnatal growth and may have prevented rapid catch-up growth later in infancy. Adiponectin concentration at 5 months CA was higher in the intervention group and correlated positively with early weight gain and nutrient supply. Early nutrition and growth may affect metabolic markers in infancy. Clinical Trial Registration (ClinicalTrials.gov) no.: NCT01103219

ESPGHAN/ESPEN/ESPR guidelines on pediatric parenteral nutrition: Energy

a Erasmus MC-Sophia Childrens Hospital, Rotterdam, The Netherlands b Newcastle Neonatal Service, Newcastle Hospitals NHS Trust & Newcastle University, Newcastle upon Tyne NE1 4LP, UK c Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China d Service Universitaire de N eonatologie, Centre Hospitalier R egional (CHR) de la Citadelle, Centre Hospitalier Universitaire (CHU) de Li ege, Universit e de Li ege, Belgium