Search

Background: Infants born moderate-to-late preterm (i.e., 32 wk-35 wk 6 d gestation) are, analogous to those born very preterm, at risk of later obesity, hypertension, and diabetes. Appropriate early life nutrition is key for ensuring optimal growth and body composition, thereby mitigating potential cardiometabolic risks., Objectives: We aimed to compare growth and body composition between infants born moderate-to-late preterm fed isocaloric but protein- and mineral-enriched postdischarge formula (PDF) or standard term formula (STF) until 6 mo corrected age (CA; i.e., after term equivalent age [TEA])., Methods: After enrollment (≤7 d postpartum), infants received PDF if (fortified) mother's own milk (MOM) was insufficient. At TEA, those receiving >25% of intake as formula were randomized to either continue the same PDF (n = 47) or switch to STF (n = 50); those receiving ≥75% of intake as MOM (n = 60) served as references. At TEA and 6 mo CA, we assessed anthropometry and body composition using both dual-energy x-ray absorptiometry (DXA) and air displacement plethysmography (ADP)., Results: Feeding groups had similar gestational age (median [25th percentile;75th percentile]: 34.3 [33.5; 35.1] wk), birthweight (mean ± standard deviation [SD]: 2175 ± 412 g), anthropometry, and body composition at TEA. At 6 mo CA, infants fed PDF had slightly, but significantly, greater length (67.6 ± 2.5 and 66.9 ± 2.6 cm, P < 0.05) and larger head circumference (43.9 ± 1.3 and 43.4 ± 1.5 cm, P < 0.05) compared to infants fed STF. Also, infants fed PDF had higher lean mass (LM) and bone mineral content estimated by DXA (4772 ± 675 and 4502 ± 741 g; 140 ± 20 and 131 ± 23 g, respectively; P < 0.05). ADP estimates, however, were not statistically different between feeding groups., Conclusions: Infants born moderate-to-late preterm demonstrated modest increases in length, head circumference, LM, and bone mineral content when fed PDF compared to STF for 6 mo after TEA. This trial was registered at the International Clinical Trial Registry Platform as NTR5117 and NTR NL4979., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To review the current literature and develop consensus conclusions and recommendations on nutrient intakes and nutritional practice in preterm infants with birthweight <1800 g., Methods: The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee of Nutrition (CoN) led a process that included CoN members and invited experts. Invited experts with specific expertise were chosen to represent as broad a geographical spread as possible. A list of topics was developed, and individual leads were assigned to topics along with other members, who reviewed the current literature. A single face-to-face meeting was held in February 2020. Provisional conclusions and recommendations were developed between 2020 and 2021, and these were voted on electronically by all members of the working group between 2021 and 2022. Where >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., Competing Interests: N.D.E. reports receipt of research grant supports from National Institutes for Health Research (UK), Prolacta Bioscience (US), Danone Early Life Nutrition, Medical Research Council, and Action Medical Research; payment/honorarium for lectures from Nestle Nutrition Institute, Astarte Medical. S.J.M. reports receipt of research support from DSM Nutritional Products and payment/honorarium for lectures from Baxter. A.L. reports receipt of lecture fees and/or nonfinancial support from Baxter, Fresenius, Nestle, and Mead Johnson Nutrition. C.H.P.v.d.A. reports receipt of speakers and consultancy honoraria from Nestlé Nutrition Institute, Nutricia Early Life Nutrition, and Baxter. V.C. reports speaker fees from Baxter and Chiesi Pharma. C.F. reports receipt of lecture fees from Nestle Nutrition Institute, Medela, Prolacta, and Neobiomics and consultancy fees for Medela, Baxter, Hipp, and Nutricia. K.G. reports receipt of research grants, speakers and consultancy fees and hospitality from Nestle Health Sciences, Nutricia-Danone, Baxter, Mylan, Dr. Falk Pharma, Abbott, Servier, and Janssen. J.B.v.G. reports a research grant from Nutrinia and FP7/Danone. Founder & Director of Dutch National Human Milk Bank and council member of National Health Council. N.H. reports consulting fees from Medis, MAM, Baxter, and Nestle and speaker fees from Nestle, Baxter, Danone, and Hipp outside the submitted work. M.J.J. reports research grants from NeoKare UK Ltd. S.M. reports research support from Nestle Health Science. L.N. reports consultancy advice for Takaeda and Nestle. J.B. reports personal fees and nonfinancial support from AbbVie, Nutricia, and Biocodex, personal fees from MSD, Nestlé, and Ferring. F.I. reports receipt of payment/honorarium for lectures from Biogaia, Nestle, Danone, and Abbot, and consultancy fees from Biogaia. E.V. reports grant/research support from Nutricia Italia Spa, Nestle Health Science – Vitaflo Italy, FoodAR srl Italy, PIAM Pharma, and Integrative Care. M.D. reports a research grant from Prolacta and speaker fees from Semper, Baxter, Mead Johnson, and Nestlé. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

n/a.

Objective: To determine the effects of lower (≤0.3) versus higher (≥0.6) initial fractional inspired oxygen (FiO 2 ) for resuscitation on death and/or neurodevelopmental impairment (NDI) in infants <32 weeks' gestation., Design: Meta-analysis of individual patient data from three randomised controlled trials., Setting: Neonatal intensive care units., Patients: 543 children <32 weeks' gestation., Intervention: Randomisation at birth to resuscitation with lower (≤0.3) or higher (≥0.6) initial FiO 2 ., Outcome Measures: Primary: death and/or NDI at 2 years of age.Secondary: post-hoc non-randomised observational analysis of death/NDI according to 5-minute oxygen saturation (SpO 2 ) below or at/above 80%., Results: By 2 years of age, 46 of 543 (10%) children had died. Of the 497 survivors, 84 (17%) were lost to follow-up. Bayley Scale of Infant Development (third edition) assessments were conducted on 377 children. Initial FiO 2 was not associated with difference in death and/or disability (difference (95% CI) -0.2%, -7% to 7%, p=0.96) or with cognitive scores <85 (2%, -5% to 9%, p=0.5). Five-minute SpO 2 >80% was associated with decreased disability/death (14%, 7% to 21%) and cognitive scores >85 (10%, 3% to 18%, p=0.01). Multinomial regression analysis noted decreased death with 5-minute SpO 2 ≥80% (odds (95% CI) 09.62, 0.98 to 0.96) and gestation (0.52, 0.41 to 0.65), relative to children without death or NDI., Conclusion: Initial FiO 2 was not associated with difference in risk of disability/death at 2 years in infants <32 weeks' gestation but CIs were wide. Substantial benefit or harm cannot be excluded. Larger randomised studies accounting for patient differences, for example, gestation and gender are urgently needed., Competing Interests: Competing interests: YR has patents for technology to guide oxygen titration during newborn resuscitation. He did not contribute to any aspects of the manuscript related to the targeting of oxygen saturation., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Feeding intolerance is a common condition among preterm infants owing to immaturity of the gastrointestinal tract. Enteral insulin appears to promote intestinal maturation. The insulin concentration in human milk declines rapidly post partum and insulin is absent in formula; therefore, recombinant human (rh) insulin for enteral administration as a supplement to human milk and formula may reduce feeding intolerance in preterm infants., Objective: To assess the efficacy and safety of 2 different dosages of rh insulin as a supplement to both human milk and preterm formula., Design, Setting, and Participants: The FIT-04 multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 46 neonatal intensive care units throughout Europe, Israel, and the US. Preterm infants with a gestational age (GA) of 26 to 32 weeks and a birth weight of 500 g or more were enrolled between October 9, 2016, and April 25, 2018. Data were analyzed in January 2020., Interventions: Preterm infants were randomly assigned to receive low-dose rh insulin (400-μIU/mL milk), high-dose rh insulin (2000-μIU/mL milk), or placebo for 28 days., Main Outcomes and Measures: The primary outcome was time to achieve full enteral feeding (FEF) defined as an enteral intake of 150 mL/kg per day or more for 3 consecutive days., Results: The final intention-to-treat analysis included 303 preterm infants (low-dose group: median [IQR] GA, 29.1 [28.1-30.4] weeks; 65 boys [59%]; median [IQR] birth weight, 1200 [976-1425] g; high-dose group: median [IQR] GA, 29.0 [27.7-30.5] weeks; 52 boys [55%]; median [IQR] birth weight, 1250 [1020-1445] g; placebo group: median [IQR] GA, 28.8 [27.6-30.4] weeks; 54 boys [55%]; median [IQR] birth weight, 1208 [1021-1430] g). The data safety monitoring board advised to discontinue the study early based on interim futility analysis (including the first 225 randomized infants), as the conditional power did not reach the prespecified threshold of 35% for both rh-insulin dosages. The study continued while the data safety monitoring board analyzed and discussed the data. In the final intention-to-treat analysis, the median (IQR) time to achieve FEF was significantly reduced in 94 infants receiving low-dose rh insulin (10.0 [7.0-21.8] days; P = .03) and in 82 infants receiving high-dose rh insulin (10.0 [6.0-15.0] days; P = .001) compared with 85 infants receiving placebo (14.0 [8.0-28.0] days). Compared with placebo, the difference in median (95% CI) time to FEF was 4.0 (1.0-8.0) days for the low-dose group and 4.0 (1.0-7.0) days for the high-dose group. Weight gain rates did not differ significantly between groups. Necrotizing enterocolitis (Bell stage 2 or 3) occurred in 7 of 108 infants (6%) in the low-dose group, 4 of 88 infants (5%) in the high-dose group, and 10 of 97 infants (10%) in the placebo group. None of the infants developed serum insulin antibodies., Conclusions and Relevance: Results of this randomized clinical trial revealed that enteral administration of 2 different rh-insulin dosages was safe and compared with placebo, significantly reduced time to FEF in preterm infants with a GA of 26 to 32 weeks. These findings support the use of rh insulin as a supplement to human milk and preterm formula., Trial Registration: ClinicalTrials.gov Identifier: NCT02510560.

Importance: Active participation in care by parents and zero separation between parents and their newborns is highly recommended during infant hospitalization in the neonatal intensive care unit (NICU)., Objective: To study the association of a family integrated care (FICare) model with maternal mental health at hospital discharge of their preterm newborn compared with standard neonatal care (SNC)., Design, Setting, and Participants: This prospective, multicenter cohort study included mothers with infants born preterm treated in level-2 neonatal units in the Netherlands (1 unit with single family rooms [the FICare model] and 2 control sites with standard care in open bay units) between May 2017 and January 2020 as part of the AMICA study (fAMily Integrated CAre in the neonatal ward). Participants included mothers of preterm newborns admitted to participating units. Data analysis was performed from January to April 2021., Exposures: FICare model in single family rooms with complete couplet-care for the mother-newborn dyad during maternity and/or neonatal care., Main Outcomes and Measures: Maternal mental health, measured using the Parental Stress Scale: NICU (PSS-NICU). Secondary outcomes included survey scores on the Hospital Anxiety and Depression Scale, Postpartum Bonding Questionnaire, Perceived Maternal Parenting Self-efficacy Scale, and satisfaction with care (using EMPATHIC-N). Parent participation (using the CO-PARTNER tool) was assessed as a potential mediator of the association of the FICare model on outcomes with mediation analyses., Results: A total of 296 mothers were included; 124 of 141 mothers (87.9%) in the FICare model and 115 of 155 (74.2%) mothers in SNC responded to questionnaires (mean [SD] age: FICare, 33.3 [4.0] years; SNC, 33.3 [4.1] years). Mothers in the FICare model had lower total PSS-NICU stress scores at discharge (adjusted mean difference, -12.24; 95% CI, -18.44 to -6.04) than mothers in SNC, and specifically had lower scores for mother-newborn separation (adjusted mean difference, -1.273; 95% CI, -1.835 to -0.712). Mothers in the FICare model were present more (>8 hours per day: 105 of 125 [84.0%] mothers vs 42 of 115 [36.5%]; adjusted odds ratio, 19.35; 95% CI, 8.13 to 46.08) and participated more in neonatal care (mean [SD] score: 46.7 [6.9] vs 40.8 [6.7]; adjusted mean difference, 5.618; 95% CI, 3.705 to 7.532). Active parent participation was a significant mediator of the association between the FICare model and less maternal depression and anxiety (adjusted indirect effect, -0.133; 95% CI, -0.226 to -0.055), higher maternal self-efficacy (adjusted indirect effect, 1.855; 95% CI, 0.693 to 3.348), and better mother-newborn bonding (adjusted indirect effect, -0.169; 95% CI, -0.292 to -0.068)., Conclusions and Relevance: The FICare model in our study was associated with less maternal stress at discharge; mothers were more present and participated more in the care for their newborn than in SNC, which was associated with improved maternal mental health outcomes. Future intervention strategies should aim at reducing mother-newborn separation and intensifying active parent participation in neonatal care., Trial Registration: Netherlands Trial Register identifier NL6175.

Background & Aims: Experimental (nutritional) interventions in preterm infants frequently focus on intestinal maturation, as improving tolerance to enteral nutrition is a major goal. Intestinal permeability and lactase activity serve as markers for intestinal maturation. We aimed to develop a protocol for the simultaneous assessment of both markers in human-milk-fed preterm infants by a sugar absorption test. In addition, we developed a new gas chromatography-mass spectrometry (GC-MS) method for the analysis of lactulose, lactose, and mannitol in urine and milk collected during the sugar absorption test., Methods: The sugar absorption test was performed on days 4, 7, and 14 postpartum in 12 preterm infants (gestational age of 26-32 weeks). Human milk was collected, pooled, and divided into equal portions to provide a stable lactose intake for 24 h. Urine was collected in the last 6 h of this 24 h period, after administration of a bolus test sugar solution. Samples were analyzed by GC-MS after derivatization by oxime formation combined with acetylation., Results: The GC-MS method was validated and used for the accurate measurement of lactulose, lactose, and mannitol concentrations. The urinary lactulose/mannitol ratio declined with time, suggesting a decreased intestinal permeability. The urine-to-milk-lactulose/lactose ratio increased as a result of increased lactase activity with time., Conclusions: The developed protocol for simultaneous assessment of intestinal permeability and lactase activity can be used to monitor the effect of experimental (nutritional) interventions in human-milk-fed preterm infants. Urine and milk samples obtained during the sugar absorption test can be accurately analyzed by GC-MS., Competing Interests: Conflict of interest J.B.v.G. is member of the National Health Council and chair of the committee on Nutrition and Pregnancy. He is director of the national Dutch Human Milk Bank. He does not receive any honorarium for his services. Other authors disclose that they have no conflicts of interests., (Copyright © 2020. Published by Elsevier Ltd.)

For preterm and small-for-gestational age infants on enteral nutrition, the best solution is to add human milk fortifier (HMF) to human milk (HM) which is provided by the mother or a milk bank. HMF provides a means to add additional protein, energy, and micronutrients, while maintaining HM as the main source of nutrition. Because of their rapid increase of lean body mass, preterm infants have much higher protein requirements than term infants. Recommendations on protein requirements of preterm infants are available, but protein quality - i.e. the amino acid (AA) profile in HMFs has not been systematically assessed. Present guidelines for enteral nutrition recommend protein intakes around 4 g/kg body weight (BW) for preterm infants <1,500 g, an intake that is not achievable with unfortified HM intakes <200 mL/kg BW/day. It is generally assumed that the AA profile of HM is the best reference for the AA profile of HMF. We calculated advisable intakes of AAs for preterm infants between 400-2,500 g which are based on AA increments of the fetus. Corrections for absorption, inevitable losses, oxidation, and variation of AAs in HM were introduced. Our calculations indicate that extremely low birth weight (ELBW <1,000 g) and very low birth weight (VLBW <1,500 g) infants have substantially higher AA requirements than low birth weight (LBW) infants growing from 1,900 to 2,400 g. In ELBW infants, daily intakes of the different indispensable AAs (IAA) with 4 g of (term) HM protein/kg BW range between 59 and 125% of the respective advisable intakes. Intakes of 7 IAAs and 3 conditionally indispensable AAs (CIAA) are below advisable intakes. On the other hand, with 4 g HM protein per kg BW/day, the IAAs isoleucine and leucine and some dispensable AAs are already supplied in abundance. In VLBW infants, daily intakes of the IAA methionine and 3 CIAAs are still below the advisable intakes. In LBW infants (<2,000 g) receiving 3.5 g HM protein per kg BW daily intakes of 1 IAA and 3 CIAAs would be too low. Preterm infants should receive HMFs which provide adequate amounts of AAs which are needed for their rapid growth and development while avoiding excessive intakes. In particular, very high AA requirements of ELBW infants are a challenge. AA composition of present HMFs for preterm infants should be reconsidered: spiking HMF protein with the AAs which are presently undersupplied or providing targeted AA-based HMF are options to further improve the AA profile in fortifiers., (© 2022 S. Karger AG, Basel.)

Mother's own milk is universally recognized as the optimal source of nutrition for preterm infants, although most authorities agree a multi-nutrient fortifier must be added in order to support nutrient accretion at a rate comparable to in utero. Nevertheless, many preterm infants face a gap between achieved growth and what could have been achieved in utero. In this narrative review, we provide an overview on the macronutrient content in mother's own milk and donor milk and how this can be enhanced by the various available multi-nutrient fortifiers. We describe their general compositions and formulation, as well as several of their theoretical and practical advantages and drawbacks. In addition, differences between standardized fortification, or a more individualized approach like adjusted and targeted fortification are discussed. The optimal strategy however remains to be elucidated, and more experimental well-powered studies are therefore urgently needed. Until then, financial considerations and practical capabilities are likely to be the main drivers of local fortification strategies., (© 2022 S. Karger AG, Basel.)

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.

Introduction: Children born from pregnancies that were complicated by hypertensive disorders of pregnancy (HDP, i.e. pre-eclampsia or HELLP syndrome) are at risk for elevated systolic and diastolic blood pressure (SBP/DBP) in childhood., Aim: To examine which neonatal, life style, and family characteristics are associated with SBP/DBP., Methods: Study design: Prospective cohort., Subjects: 12-years-old preterm and growth restricted children born to women with severe early-onset HDP., Outcome Measures: SBP/DBP standard deviation scores (SDS), corrected for age, gender and height., Results: Ninety-two of the 174 mother-child pairs participated at age 12 years (mean gestational age 32 weeks, range 27 to 38 weeks, mean birth weight ratio (BWR) 0.68, range 0.33 to 0.99). Mean SBP SDS was 0.70 ± 0.81 and mean DBP SDS was 0.14 ± 0.78. SBP SDS was positively associated with very preterm birth (beta 0.53, p = .002), with child BMI SDS (beta 0.25, p = .035), and maternal BMI ≥ 25 kg/m 2 at 12 years (beta 0.49, p = .003), and not with pre-pregnancy maternal BMI ≥ 25 kg/m 2 . DBP SDS was positively associated with maternal BMI ≥ 25 kg/m 2 (beta 0.35, p 0.002). BWR was not associated with blood pressure., Conclusions: In 12-years old children born to women with HDP, higher systolic blood pressure values were associated with very preterm birth and child BMI. Higher blood pressure values were also associated with current maternal BMI ≥ 25 kg/m 2 . Life style adaptations may benefit long-term cardio vascular health in mother and child., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Late-onset sepsis (LOS) in preterm infants is a leading cause of mortality and morbidity. Timely recognition and initiation of antibiotics are important factors for improved outcomes. Identification of risk factors could allow selection of infants at an increased risk for LOS., Objectives: The aim was to identify risk factors for LOS., Methods: In this multicenter case-control study, preterm infants born at ≤30 weeks of gestation were included at 9 neonatal intensive care units. Detailed demographical and clinical data were collected daily up to day 28 postnatally. Clinical and demographic risk factors were identified using univariate and multivariate regression analyses in a 1: 1 matched case-control cohort., Results: In total, 755 infants were included, including 194 LOS cases (41 gram-negative cases, 152 gram-positive cases, and 1 fungus). In the case-control cohort, every additional day of parenteral feeding increased the risk for LOS (adjusted OR = 1.29; 95% CI 1.07-1.55; p = 0.006), whereas antibiotics administration decreased this risk (OR = 0.08; 95% CI 0.01-0.88; p = 0.039). These findings could largely be attributed to specific LOS-causative pathogens, since these predictive factors could be identified for gram-positive, but not for gram-negative, LOS cases. Specifically cephalosporins administration prior to clinical onset was inversely related to coagulase-negative staphylococcus LOS (CoNS-LOS) development. Formula feeding was an independent risk factor for development of CoNS-LOS (OR = 3.779; 95% CI 1.257-11.363; p = 0.018)., Conclusion: The length of parenteral feeding was associated with LOS, whereas breastmilk administration was protective against CoNS-LOS. A rapid advancement of enteral feeding, preferably with breastmilk, may proportionally reduce the number of parenteral feeding days and consequently the risk for LOS., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background: The intestinal microbiota has increasingly been considered to play a role in the etiology of late-onset sepsis (LOS). We hypothesize that early alterations in fecal volatile organic compounds (VOCs), reflecting intestinal microbiota composition and function, allow for discrimination between infants developing LOS and controls in a preclinical stage., Methods: In 9 neonatal intensive care units in the Netherlands and Belgium, fecal samples of preterm infants born at a gestational age ≤30 weeks were collected daily, up to the postnatal age of 28 days. Fecal VOC were measured by high-field asymmetric waveform ion mobility spectrometry (FAIMS). VOC profiles of LOS infants, up to 3 days prior to clinical LOS onset, were compared with profiles from matched controls., Results: In total, 843 preterm born infants (gestational age ≤30 weeks) were included. From 127 LOS cases and 127 matched controls, fecal samples were analyzed by means of FAIMS. Fecal VOCs allowed for preclinical discrimination between LOS and control infants. Focusing on individual pathogens, fecal VOCs differed significantly between LOS cases and controls at all predefined time points. Highest accuracy rates were obtained for sepsis caused by Escherichia coli, followed by sepsis caused by Staphylococcus aureus and Staphylococcus epidermidis., Conclusions: Fecal VOC analysis allowed for preclinical discrimination between infants developing LOS and matched controls. Early detection of LOS may provide clinicians a window of opportunity for timely initiation of individualized therapeutic strategies aimed at prevention of sepsis, possibly improving LOS-related morbidity and mortality.

Objectives: Several randomized controlled trials (RCTs) on the use of probiotics to reduce morbidity and mortality in preterm infants have provided inconsistent results. Although meta-analyses that group all of the used strains together are suggesting efficacy, it is not possible to determine the most effective strain that is more relevant to the clinician. We therefore used a network meta-analysis (NMA) approach to identify strains with greatest efficacy., Methods: A PubMed search identified placebo-controlled or head-to-head RCTs investigating probiotics in preterm infants. From trials that recorded mortality, necrotizing enterocolitis, late-onset sepsis, or time until full enteral feeding as outcomes, data were extracted and Bayesian hierarchical random-effects models were run to construct a NMA., Results: Fifty-one RCTs involving 11,231 preterm infants were included. Most strains or combinations of strains were only studied in one or a few RCTs. Only 3 of 25 studied probiotic treatment combinations showed significant reduction in mortality rates. Seven treatments reduced necrotizing enterocolitis incidence, 2 reduced late-onset sepsis, and 3 reduced time until full enteral feeding. There was no clear overlap of strains, which were effective on multiple outcome domains., Conclusions: This NMA showed efficacy in reducing mortality and morbidity only in a minority of the studied strains or combinations. This may be due to an inadequate number, or size, of RCTs, or due to a true lack of effect for certain species. Further large and adequately powered RCTs using strains with the greatest apparent efficacy will be needed to more precisely define optimal treatment strategies.

Objectives: Mother's own milk (MM) is the best nutrition for newborn preterm infants, but is often limited in supply just after birth. Pasteurized human donor milk (DM), and especially preterm infant formula (IF) are less optimal diets than MM. We hypothesized that it is feasible to use bovine colostrum (BC), the first milk from cows, as a supplement to MM, during the first weeks after preterm birth., Methods: In an open-label, randomized, controlled pilot safety trial, supplementation of MM with BC was compared with DM supplementation (Danish unit) or IF supplementation (Chinese unit). If MM was limited or lacking, BC, DM or IF were given according to local feeding guidelines during the first 14 days of life., Results: Forty infants were included and randomized in Denmark and in China, with gestational ages 29.9 ± 0.4 and 31.1 ± 0.2 weeks, respectively. Infants supplemented with BC received more enteral protein (P < 0.05) and tended to reach full enteral feeding earlier (China only). Eight infants fed BC showed a temporary elevation in plasma tyrosine on day 7, versus 2 infants in the DM/IF groups. There were no differences between diet groups in feeding intolerance or clinical adverse events., Conclusions: Our results indicate that it is feasible to use BC as a supplement to MM during the first weeks of life to increase enteral protein intake in preterm infants. Plasma tyrosine levels may be a good marker for excessive protein intake. A larger randomized trial is required to test the safety and possible short- and long-term clinical benefits of BC supplementation during the first weeks of life for preterm infants.

As technology has advanced, survival rates of preterm infants have improved dramatically. Human milk was the primary source of enteral nutrition during the early days of neonatology, but the HIV/AIDS epidemic resulted in an increased use of preterm formula. More recently, the benefits of human milk were rediscovered, resulting in increased use of donor human milk as well. The awareness that human milk does not contain the amounts of nutrients to meet the high requirements of infants born premature resulted in the development of human milk fortifiers. The development of these fortifiers is still ongoing, as are alternative methods of pasteurization of donor milk. Those initiatives will increase the use of human milk with consequently short- and long-term benefits for preterm infants., (© 2018 S. Karger AG, Basel.)

Background: What is the appropriate time to start complementary feeding for preterm infants? The answer to this question is yet under debate. The timing of initiating complementary feeding may be associated with overweight in term infants. This systematic review aimed to study the effect of the timing of initiating complementary feeding on overweight in preterm infants. Predefined search items included preterm infants, complementary feeding, overweight, and their synonyms., Summary: The search identified 15,749 articles, of which 5 articles were included. Three studies presented data of randomized controlled trials and 2 studies were cohort studies. Two randomized controlled trials found no significant difference in body mass index (BMI) Z-score between the intervention groups at 12 months of age. One randomized controlled trial presented a significant greater mean rate of growth in length per week until 12 months in the preterm weaning strategy-group compared with the current best practices. One observational study concluded that each month the infants received complementary food later, the Z-score for length and weight was reduced by 0.1. Key Messages: No clear conclusion could be drawn from the included studies. This review illustrates the need for further research to access the effect of the timing of initiating complementary feeding on overweight in preterm infants., (© 2018 S. Karger AG, Basel.)

Preterm infants often have a reduced bone mineral content (BMC) with increased risk of metabolic bone disease. After birth it is difficult to supply calcium (Ca) and phosphorus (P) comparable to the high fetal accretion rate. It is not known whether high supplementation of minerals in the early postnatal period improves growth and bone mineralization. The aim of this study was to evaluate growth and bone mineralization at term corrected age (TCA) in very and extremely preterm infants who received different enteral Ca and P intakes during the first 10 days of life. Infants ( n = 109) with birth weights below 1500 g were randomly assigned to one of three groups that differed in the nutritional protocols delivered until day 10: Group A, mother's own milk (MOM) and donor milk (unfortified); Group B, MOM (unfortified) and preterm formula; Group C, MOM (start fortification >50 mL/day) and preterm formula. Due to the earlier commencement of fortification, Group C received higher intakes of calcium and phosphorus and protein ( p < 0.001) until day 10. At TCA weight, length, BMC and bone mineral density (BMD), measured by dual-X-ray absorptiometry, were not different between the groups. Nutritional intake of P was positively associated with length (β; (95% confidence interval (CI): 0.20 (0.001; 0.393); p -value = 0.048), whereas Ca intake was negatively associated with BMC (-1.94 (-2.78; -1.09); p -value < 0.001). A small interaction between Ca and P intake was only found for BMD (0.003 (0.00002; 0.00006); p -value = 0.036). The volume of human milk per kg provided during the first 10 days was positively associated with BMC (β; (95% CI): 0.013 (0.002; 0.023); p < 0.017). Higher intakes of Ca and P during the first 10 days, as provided in this study, did not improve bone mineralization at term corrected age., Competing Interests: The authors declare no conflict of interest. Johannes B. Van Goudoever reports grants outside the submitted work from Mead Johnson Nutrition, during the conduct of the study, grants from EU, FP-7 programme. Johannes B. Van Goudoever serves as director of the National Human Milk bank and as board member of the National Health Council and the National Breastfeeding Committee.

Introduction: Preterm infants are at an increased risk for neurodevelopmental delay. They have to endure many stressors in early life, including parent-infant separation, noise and painful procedures during hospitalisation in the highly technological environment of the modern neonatal ward. Currently, a shift is being noticed in the architectural design of neonatal wards towards single family rooms instead of the common open bay units. The influence of the hospital environment on health and specifically neurodevelopment in this vulnerable patient population remains under discussion., Objectives: To assess the effect of single family rooms during hospitalisation primarily on neurodevelopment in preterm infants. Secondary outcome measures will be neonatal (ie, breastfeeding rates, sepsis, growth during hospital stay, length of hospital stay) and parental (ie, parental stress, satisfaction, participation, presence and self-efficacy)., Methods and Analysis: The PRISMA-P 2015 (Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015) 17 items checklist was used for the generation of the protocol for this review. The following PICO was formulated: Population: preterm infants with need of hospitalisation in the neonatal ward; Intervention: single family rooms; Comparison: standard neonatal care in open bay units; Outcome: neurodevelopmental outcome of infants from 9 months onwards. If at least two studies, with low or moderate risk of bias, suitable for inclusion are found a meta-analysis will be performed. If quantitative synthesis is not appropriate the data will be presented descriptively., Dissemination Plans: This will be the first review, systematically assessing the effect of single family rooms on neurodevelopmental outcome in preterm infants. Clinical practice could possibly be optimised to ameliorate neurodevelopment in this vulnerable patient population based on these insights. This systematic review will be published in an international peer-reviewed journal., Registration: We registered this systematic review protocol with the PROSPERO (International Prospective Register of Systematic Reviews) on 2 November 2016 (registration number: CRD42016050643)., Ethics: We will use data from patients enrolled in studies and/or trials already approved by the relevant ethical committees and therefore this systematic review requires no further permissions., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Early growth rates and feeding advancement rates of preterm infants are thought to influence later health. Feeding advancement is often difficult because of feeding intolerance. Exclusive human milk feeding improves tolerance, but can result in a lower weight gain rate. The addition of human milk fortifier has advantages for growth, but there are concerns that it may nullify the beneficial effect of human milk on tolerance. Therefore, the objective of the present study was to evaluate the relation between the amount of fortified human milk or formula and feeding tolerance and growth in preterm infants., Methods: Patients (n = 174) participating in the TOL trial and born with a gestational age 30 weeks or younger were divided into tertiles according to the amount of human milk received during feeding advancement. Data on feeding tolerance during the advancement phase of enteral nutrition and anthropometrics were analysed., Results: The infants (n = 59) receiving the lowest percentage of their enteral intake as human milk (0%-57%) had the lowest amount of gastric residuals (P = 0.034) compared with the other 2 tertiles. Time to reach full enteral feeding and other tolerance parameters were not different among the groups. There was no dose response effect of the amount of human milk consumed on growth., Conclusions: In preterm infants, an association between type of feeding (human milk vs infant formula) and time to achieve full enteral feeding or short-term growth was not found. Future prospective trials are needed to verify our results and focus on means to improve tolerance further.

Background: In term infants, there is evidence that early complementary feeding is a risk factor for childhood obesity. Therefore, timely introduction of complementary feeding during infancy is necessary. The World Health Organization (WHO) and European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) both developed recommendations for the start of complementary feeding for term-born infants. However, these guidelines cannot be directly translated to preterm infants. Recent literature looking at the introduction of complementary feeding in preterm infants gives contrasting information. Given these contrasting reports on the introduction of solid foods in premature born infants, a systematic review is needed. The primary objective of this study is to analyze the effect of the time starting complementary feeding on overweight (including obesity) in preterm infants., Methods: An electronic systematic literature search with pre-defined terms will be conducted in Cochrane, PubMed, EMBASE, Web of Science, Scopus, and CINAHL. There will be no restriction for time period. Primarily, data from randomized controlled trials (RCTs) will be included in this systematic review. Search terms will include preterm infants, complementary feeding, overweight, and their synonyms. Article selection, including risk of bias assessment, will be performed by three reviewers independently. Body mass index standard deviation score (BMI-SDS or BMI-Z-score) will be used to compare studies. The consistency of results across the studies will influence the decision whether or not to combine results in a meta-analysis. Studies that cannot be included in the meta-analysis will be described in a narrative analysis., Discussion: This systematic review will give an overview of the existing knowledge on the timing of complementary feeding in preterm infants and the effect on overweight. It will form a basis for future guidelines for complementary feeding for preterm infants., Systematic Review Registration: PROSPERO CRD42015014215.

The ultimate goal of neonatal nutrition care is optimal growth, neurodevelopment, and long-term health for preterm babies. International consensus is that increased energy and protein intakes in the neonatal period improve growth and neurodevelopment, but after more than 100 y of research the optimum intakes of energy and protein remain unknown. We suggest an important factor contributing to the lack of progress is the lack of a standardized approach to reporting nutritional intake data and growth in the neonatal literature. We reviewed randomized controlled trials and observational studies documented in MEDLINE and the Web of Science from 2008 to 2015 that compared approximately 3 vs. 4 g.kg(-1).d(-1) protein for preterm babies in the first month after birth. Consistency might be expected in the calculation of nutritional intake and assessment of growth outcomes in this relatively narrow scope of neonatal nutrition research. Twenty-two studies were reviewed. There was substantial variation in methods used to estimate and calculate nutritional intakes and in the approaches used in reporting these intakes and measures of infant growth. Such variability makes comparisons amongst studies difficult and meta-analysis unreliable. We propose the StRONNG Checklist-Standardized Reporting Of Neonatal Nutrition and Growth to address these issues.

Background: Preterm infants are at risk of iron deficiency (ID). Hepcidin has been suggested as a good additional indicator of ID in preterm infants, next to ferritin., Methods: In a prospective observational study, we analyzed serum hepcidin in 111 infants born after 32+0 to 36+6 wk gestational age during the first 4 mo of life., Results: Hepcidin concentrations decreased during the first 4 mo of life, and concentrations were lower in infants with ID compared to those without ID. Infants who developed ID at the age of 4 mo had already significantly lower levels of hepcidin at 1.5 mo of age, while ferritin was already significantly lower at the age of 1 wk., Conclusion: Hepcidin concentrations of late preterm infants decrease during the first 4 mo of life. This decrease, which parallels a decrease of ferritin concentration, we interpret as a physiological response, aiming to increase iron availability. Hepcidin concentrations are lower in infants with ID compared with those without ID, with a notable change already observed at 1.5 mo of age. Hepcidin can be used as an early marker of ID, although an additive value of hepcidin over ferritin in the diagnosis of ID is not present.

Objectives: The aim of the present study was to assess the clinical benefits and risks of semicontinuous (CON) versus intermittent nasogastric tube feeding in low-birth-weight infants., Methods: Infants with a birth weight <1750 g and gestational age <32 weeks were stratified according to birth weight and assigned to either CON or intermittent bolus (BOL) feeding. The primary endpoint was days to full enteral feeding (defined as 120 mL(-1) · kg(-1) · day(-1)). We also collected data on feeding tolerance, weight gain, respiratory support, and complications (sepsis, necrotising enterocolitis, and death)., Results: There was no difference between the 2 groups (CON n = 121, BOL n = 125) in days to reach full enteral feeding--7 (5-10) versus 6 (5-8) days, respectively, with a difference 1 (-0.05 to 2.1). Mean daily gastric residual volumes, however, were significantly lower in the BOL group (4.8 vs 3.9 mL/day, difference 0.9 mL/day [0.1-1.7]), as was the total number of patients with feeding interruptions (76 vs 59, difference 16% [3%-28%])., Conclusions: Bolus and continuous feeding are equally suitable feeding strategies for preterm neonates. BOL feeding, however, may be preferable.

Preterm infants have an immature antioxidant system; however, they frequently require supplemental oxygen. Oxygen-free radicals cause both pulmonary and systemic inflammation, and they are associated with increased morbidity and mortality. Consequently, screening of metabolite profiles representing the amount of lipid peroxidation is considered of great relevance for the evaluation of in vivo oxidative stress and derived inflammation and damage. Ranges for total relative contents of isoprostanes (IsoPs), isofurans (IsoFs), neuroprostanes (NeuroPs), and neurofurans (NeuroFs) within targeted SpO2 ranges were determined in urine samples of 254 preterm infants<32 weeks of gestation within the frame of two randomized, controlled, and blinded clinical trials employing ultra-performance liquid chromatography-tandem mass spectrometry. A total of 536 serial urine samples collected during the first 4 weeks after birth in recruited infants who did not develop free radical associated conditions were analyzed. A reference range for lipid peroxidation byproducts, including isoprostanes, isofurans, neuroprostanes, and neurofurans, was calculated and possible correlations with neonatal conditions were investigated. Urinary elimination of isofurans in the first 4 days after birth correlated with later development of bronchopulmonary dysplasia. Our observations lead to the hypothesis that early urinary determination of lipid peroxidation byproducts, especially isofurans, is relevant to predict development of chronic lung conditions.

Postnatal growth failure is still one of the most commonly observed morbidities in preterm infants. Intolerance of enteral nutrition is a common problem in these infants and in neonates with surgical conditions. Therefore, adequate parenteral nutrition is crucial to support organ development, including that of the brain. Short-term studies on the early introduction of parenteral lipids have demonstrated that early lipid administration seems safe and well tolerated and prevents essential fatty acid deficiency. Further well-designed and adequately powered studies are necessary to determine the optimal dose of lipid infusion and the long-term effects on morbidity, growth, and neurodevelopment. Administration of a pure soybean oil emulsion might result in excess formation of proinflammatory eicosanoids and peroxidation, and their use reduces the availability of the long-chain polyunsaturated fatty acids necessary for central nervous system development and immune function. Alternatives to the use of pure soybean oils include emulsions with partial replacement of soybean oil with medium-chain triglycerides, olive oil, and/or fish oil. These newer lipid emulsions offer many theoretical advantages. Future large-scale randomized controlled trials in premature infants should demonstrate whether these newer lipid emulsions are truly safe and result in improved short- and long-term outcomes. It seems safe to start lipid emulsions from birth onward at a rate of 2 g lipids/kg/day (based on short-term results only). Mixed lipid emulsions, including those containing fish oil, seem to reduce nosocomial infections in preterm infants and might reduce bile acid accumulation. Liver damage may be reduced by decreasing or removing lipids from parenteral nutrition or may be reduced by using fish oil-containing lipid emulsions containing high levels of vitamin E., (© 2015 S. Karger AG, Basel.)

Objective: 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., Methods: Infants born <32 weeks' gestation and <1500 g were randomized to receive glucose (n = 69) or glucose with 2.4 g · kg(-1) · day(-1 amino acids) (n = 63) from birth. From postnatal day 3 onward, the nutritional intake was similar. At 2 years of corrected age, the surviving infants were assessed for neurodevelopmental outcome and anthropometry., Results: Ninety-seven percent of the surviving infants were examined at follow-up, with no overall effect on survival without major disabilities. Boys, however, had a normal outcome significantly more often if amino acids were administered from birth onward (crude odds ratio 3.8, 95% confidence interval 1.3-11.4) and following adjustment for confounders (odds ratio 6.2, 95% confidence interval 1.0-38.0). The secondary outcomes exhibited no differences in anthropometric data. The mental developmental index was lower in the small number of girls who survived without major disabilities following the early administration of amino acids., Conclusions: In this hypothesis-generating outcome study, premature boys, but not girls, benefited from amino acid administration directly following birth. The observed lower mental developmental index in a subgroup of girls, however, warrants further studies.

Objective: To test the hypothesis that an initial fraction of inspired oxygen (FiO2) of 30% during resuscitation of preterm infants results in less oxidative stress and is associated with improved clinical outcomes compared with an FiO2 of 65%., Study Design: Preterm infants of gestational age <32 weeks (n = 193) were randomized to start resuscitation with either 30% oxygen (low-oxygen group) or 65% oxygen (high-oxygen group), after which the FiO2 was adjusted based on oxygen saturation values. The primary outcome was bronchopulmonary dysplasia (BPD) assessed at 36 weeks postmenstrual age. Secondary outcomes included major neonatal illnesses and markers of oxidative stress., Results: The median gestational age of included infants was 28(6)/7 weeks (IQR, 26(5)/7-30(3)/7 weeks). The incidence of BPD was not significantly different between the low-oxygen and high-oxygen groups (24% vs. 17%; P = .15). The FiO2 in both groups was adjusted to a mean of 40% by 7 minutes in the low-oxygen group and by 11 minutes in the high-oxygen group. No differences in markers of oxidative stress were noted between groups., Conclusion: Initial supplementation of preterm infants with 30% oxygen during the fetal-to-neonatal transition is as safe as 65% oxygen, with no differences in oxidative stress markers or BPD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Bone mineralisation in preterm infants is related to the supply of calcium (Ca) and phosphorus (P). We increased the amount of minerals in parenteral nutrition (PN) for preterm infants and evaluated postnatal Ca and P metabolism in relation to mineral and vitamin D (vitD) intake., Methods: Preterm infants, included on their first day of life, received standard PN, providing a maximum Ca/P intake of 3/1.92 mmol · kg(-1) · day(-1) on day 3. Ca/P content of formula was 2.5/1.6 mmol/dL, and fortified human milk was 2.4/1.95 mmol/dL. PN supplied 80 IU · kg(-1) · day(-1) vitD. Formula and fortified human milk contained 200 IU/dL of vitD. During a 5-week period, serum concentrations and urinary excretion of Ca/P were registered and related to the intake of minerals and vitD., Results: During 12 months, 79 infants (mean gestational age 29.8 ± 2.2 weeks, mean birth weight 1248 ± 371 g) were included. The recommended intake for minerals was achieved by day 5 and for vitD by 4 weeks. Infants developed hypercalcaemia, hypercalciuria, and hypophosphataemia during the first postnatal week, leading to the additional P supplementation in 49 infants. The renal tubular reabsorption of P was >95% until day 9 but decreased <70% after the second week. Alkaline phosphatase was normal at birth, increased to a maximum of 450 IU/L by day 14, and remained above the normal range for the remaining period., Conclusions: Parenteral intake of P appeared to be too low, leading to mineral imbalances in the early postnatal period, and vitD intake was also below recommendations.

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

Background: We determined the effect of adaptation to the study diet on oxidation of the indicator amino acid and the required tracer washout time in preterms., Methods: Subjects received a study diet for 6 d that entailed a 50% reduction in leucine. Tracer studies using enterally infused [(13)C]bicarbonate and [1-(13)C]phenylalanine were performed on days 1, 2, 4, and 6. Breath samples containing (13)CO2 were collected during steady state and measured by infrared spectrometric analysis, and the fraction of (13)CO2 recovery from (13)C oxidation (F(13)CO2) was calculated., Results: Preterm infants (n = 11, birth weight 1.9 ± 0.1 kg, gestational age 32.6 ± 1.5 wk) received 166 mg/kg/d of leucine. Baseline enrichment changed significantly at day 1 of the study diet. F(13)CO2 did not change significantly between days 2 and 4 but was significantly lower at day 6. The tracer washout time was determined to be 7.5 h using a biphasic regression analysis., Conclusion: One day of adaptation to a new diet is necessary to adapt to the (13)C enrichment of the study formula before starting infant requirement studies. Adaptation for a period of 5 d results in a protein-sparing response. The minimal time between two studies within the same subject is 7.5 h.

The cause of growth restriction in preterm infants is multifactorial, but it has been estimated that about 50% of the variance in early postnatal growth can be attributed to nutrition. Very low birth weight (VLBW) infants who were born small-for-gestational age (SGA) seem to have the highest risk to become growth restricted. Possibly, the intrauterine growth-retarded preterm infant is metabolically different from its appropriately grown counterpart and therefore has different nutritional needs. Neonatal nutrition and the resulting postnatal growth are major determinants in the short- and long-term outcomes of preterm neonates. Although having favorable effects on neurodevelopmental outcome, rapid postnatal weight gain after a period of nutritional restriction is associated with the development of insulin resistance and metabolic syndrome in later life. It seems likely that minimization of postnatal growth failure will decrease the need for catch-up growth and thereby decrease the risk of developing cardiovascular risk factors. Monitoring postnatal growth with current growth charts is complicated. Most growth charts that are currently being used are a reflection of current (nutritional) practices and are not a prescription of how VLBW should grow under optimal conditions. In addition to body weight, other aspects of growth such as lean body mass and length gain should also be taken into account when assessing the quality of postnatal growth. Noninvasive measurements of infant body composition are useful tools in evaluating the success of different nutritional interventions. However, all currently available methods have substantial drawbacks. A relatively new and promising method is air displacement plethysmography. This method still needs to be validated in preterm neonates. In conclusion, neonatal nutrition is a major determinant in the short- and long-term outcomes of preterm neonates. Monitoring postnatal growth is complicated by the lack of prescriptive growth charts and noninvasive measurements to assess the quality of growth., (Copyright © 2013 S. Karger AG, Basel.)

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

Background: Resuscitation at birth with 100% oxygen is known to increase the oxidative burden with concomitant deleterious effects. Although fractions of inspired oxygen (FiO₂) < 100% are widely used in preterm infants, starting resuscitation at a (too) low FiO₂ may result in hypoxia. The objective of this study is to compare the safety and efficacy of resuscitating very preterm infants with an initial FiO2 of 30% versus 65%., Methods/design: In this double-blind, randomized controlled trial, 200 very preterm infants with a gestational age < 32 weeks will be randomized to start resuscitation after birth with either 30% or 65% oxygen. The FiO₂ will be adjusted based on oxygen saturation measured by pulse oximetry (SpO₂) and pulse rate (which should be over 100 beats per minute) in order to achieve a target SpO₂ of 88-94% at 10 min of life. The FiO₂ and pulse oximetry data will be continuously recorded.The primary outcome is survival without bronchopulmonary dysplasia, as assessed by a physiological test at 36 weeks postmenstrual age. The secondary outcomes include the time to achieve SpO₂ > 88%, Apgar score at 5 min, cumulative O₂ exposure, oxidative stress (as determined by glutathione synthesis and oxidative stress markers), retinopathy of prematurity, brain injury and neurodevelopmental outcome at 2 years of age.This study will provide insight into determining the appropriate initial FiO₂ to start resuscitation of very preterm infants., Trial Registration: http://www.trialregister.nl, NTR243.

Infants born prematurely have an enhanced intestinal permeability compared to healthy term infants. This enhanced permeability might be a contributing factor in the development of Necrotising Enterocolitis. The assessment of intestinal permeability in premature neonates with sugar absorption tests has been proven to be safe and of minimal burden to the infant. After enteral administration of a test solution containing lactulose and mannitol, the excretion of these sugars is measured in urine, and the ratio is calculated. The lactulose and mannitol concentrations in urine can be measured by the use of a gas chromatograph after pre-purification and derivatisation of the sample. Non-invasive assessment of intestinal permeability can be useful in monitoring the effects of experimental (nutritional) therapy.

Background & Aims: The intestine is a major site of amino acid metabolism, especially in neonates. Neonatal animals derive energy needed for metabolic processes from dietary glucose and amino acids. Rats were found to oxidize non-essential amino acids such as aspartate, glutamate and glutamine in the intestine at a high rate. We have previously found that glutamate and glucose are important sources of energy for the splanchnic tissues in fully fed preterm infants. However, no data are available on splanchnic aspartate metabolism in human preterm infants. In the present study we studied whole-body and splanchnic aspartate metabolism and determined the metabolic fate of aspartate., Methods: In eight, enterally fed, preterm infants (gestational age 31 weeks (wk)+/-3 SD, range: 26-34wk) splanchnic and whole-body aspartate kinetics were assessed by dual tracer ([U-(13)C]aspartate and [D(3)]aspartate) techniques., Results: Splanchnic first-pass aspartate uptake was almost complete (77+/-15%). Almost all (80+/-9%) of the (13)C administered as [U-(13)C]aspartate used in first-pass was recovered as CO(2) in expired breath., Conclusion: The splanchnic tissues extract almost all of the dietary aspartate in preterm infants. The majority of the labeled carbon is recovered in expired breath, making it most likely that the sequestered carbon skeleton of aspartate is utilized for energy generation., (Copyright 2009 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

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.

Preterm infants have diminished antioxidant defenses. Glutathione (GSH), the main intracellular antioxidant, increases upon amino acid (AA) administration in preterm infants, without an accompanying rise of the fractional synthesis rate of GSH (FSRGSH) This study investigated the mechanism behind this increased GSH concentration by determining GSH synthesis in the first days after birth using stable isotope techniques in very low-birth-weight (VLBW) infants receiving i.v. AAs. Advanced oxidized protein products (AOPPs) were determined to quantify oxidative stress. Eighteen infants (birth weight 989 +/- 241 g, gestational age of 27/7 +/- 1/7 weeks) were studied either on postnatal day 1 or 2 (7 or 31 h postnatally, respectively). Concentration of GSH increased with postnatal age (1.45 +/- 0.48 mM versus 1.99 +/- 0.40 mM, p = 0.019). FSRGSH was not significantly different, but the absolute synthesis rate of GSH (ASRGSH) tended to be higher in the infants studied on day 2 [8.1 +/- 2.7 mg/(kg . d) versus 10.6 +/- 2.4 mg/(kg . d), p = 0.054]. AOPP concentrations were not different between groups. In conclusion, GSH concentration in VLBW infants increases significantly after birth. A concomitant increased synthesis rate was not found, suggesting that GSH consumption decreases upon AA administration.

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 extent, 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 + or - SD birth weight 1.07 + or - 0.22 kg and GA 29 + or - 2 wk) were studied by dual tracer ([U-(13)C]glutamine and [(15)N(2)]glutamine) cross-over techniques on two study days (at postnatal week 3 + or - 1 wk). Splanchnic and whole-body glutamine kinetics were assessed by plasma isotopic enrichment of [U-(13)C]glutamine and [(15)N(2)]glutamine and breath (13)CO(2) enrichments. Mean fractional first-pass glutamine uptake was 73 + or - 6% and 57 + or - 17% on the study days. The splanchnic tissues contributed for a large part (57 + or - 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.