Increased risk of refeeding syndrome-like hypophosphatemia with high initial amino acid intake in small-for-gestational-age, extremely-low-birthweight infants.

BACKGROUND: Recent nutrition guidelines for extremely-low-birth-weight infants (ELBWIs) recommend implementation of high initial amino acid (AA) supplementation in parenteral nutrition. OBJECTIVE: We sought to evaluate the influence of AA intake on refeeding syndrome-like electrolyte disturbances including hypophosphatemia in ELBWIs. STUDY DESIGN: Medical records of 142 ELBWIs were reviewed. Demographic, nutritional, outcome, and electrolyte data were compared between ELBWIs with initial low (1.5 g/kg/day) and high (3 g/kg/day) AA intake. Multivariate analysis was conducted to determine the odds ratio of hypophosphatemia with high AA intake and small-for-gestational-age (SGA) ELBWIs. RESULTS: The incidence of hypophosphatemia and severe hypophosphatemia increased from 51% and 8% in period I to 59% and 20% in period II, respectively (p = 0.36 and < 0.01). Specifically, SGA ELBWIs showed higher incidence of hypophosphatemia than appropriate-for-gestational age (AGA) ELBWIs in period II, whereas there was no difference in period I. For severe hypophosphatemia, SGA ELBWIs presented a 27% incidence versus a 2% incidence in AGA ELBWIs, even with low initial AA intake. Despite no difference in phosphate intake between infants with and without hypophosphatemia, serum phosphate level reached a nadir at the sixth postnatal day and gradually recovered over the second week in infants with hypophosphatemia. In multivariate analyses, the odds ratios for severe hypophosphatemia were 3.6 and 6.6 with high AA intake and SGA status, respectively, with the highest being 18.0 with combined high AA intake and SGA status. CONCLUSIONS: In summary, high initial AA intake significantly increased the risk of refeeding syndrome-like electrolyte dysregulations including severe hypophosphatemia in ELBWIs. In SGA ELBWIs, the risk of electrolyte disturbance was significantly higher, even with low initial AA intake. Therefore, new tailored parenteral nutrition protocols starting with lower energy intake and a gradual increase over the first week may be warranted for application in high-risk SGA ELBWIs.

Growth, Feeding Tolerance and Metabolism in Extreme Preterm Infants under an Exclusive Human Milk Diet.

BACKGROUND: For preterm infants, human milk (HM) has to be fortified to cover their enhanced nutritional requirements and establish adequate growth. Most HM fortifiers are based on bovine protein sources (BMF). An HM fortifier based on human protein sources (HMF) has become available in the last few years. The aim of this study is to investigate the impact of an HMF versus BMF on growth in extremely low birth weight (ELBW, <1000 g) infants. METHODS: This was a retrospective, controlled, multicenter cohort study in infants with a birthweight below 1000 g. The HMF group received an exclusive HM diet up to 32+0 weeks of gestation and was changed to BMF afterwards. The BMF group received HM+BMF from fortifier introduction up to 37+0 weeks. RESULTS: 192 extremely low birth weight (ELBW)-infants were included (HMF n = 96, BMF n = 96) in the study. After the introduction of fortification, growth velocity up to 32+0 weeks was significantly lower in the HMF group (16.5 g/kg/day) in comparison to the BMF group (18.9 g/kg/day, p = 0.009) whereas all other growth parameters did not differ from birth up to 37+0 weeks. Necrotizing enterocolitis (NEC) incidence was 10% in the HMF and 8% in the BMF group. CONCLUSION: Results from this study do not support the superiority of HFM over BMF in ELBW infants.

Pharmacometabolomics of Respiratory Phenotypic Response to Dexamethasone in Preterm Infants at Risk for Bronchopulmonary Dysplasia.

A prospective cohort study was performed in preterm infants less than 32 weeks gestation at birth who were treated with dexamethasone for developing or established bronchopulmonary dysplasia (BPD). Respiratory phenotype (Respiratory Severity Score (RSS)), serum, and urine metabolomics were assessed before and after treatment. Ten infants provided nine matched serum and nine matched urine samples. There was a significant decrease in RSS with steroid treatment. Serum gluconic acid had the largest median fold change (140 times decreased, P = 0.008). In metabolite set enrichment analysis, in both serum and urine, the urea cycle, ammonia recycling, and malate-aspartate shuttle pathways were most significantly enriched when comparing pretreatment and post-treatment (P value < 0.05). In regression analyses, 6 serum and 28 urine metabolites were significantly associated with change in RSS. Urine gluconic acid lactone was the most significantly correlated with clinical response (correlational coefficient 0.915). Pharmacometabolomic discovery of drug response biomarkers in preterm infants may allow precision therapeutics in BPD treatment.

Predictive value of the aspartate aminotransferase to platelet ratio index for parenteral nutrition associated cholestasis in extremely low birth weight infants.

BACKGROUND: Parenteral nutrition (PN) improves the survival of premature infants. However, prolonged PN increases the risk of PN-associated cholestasis (PNAC). OBJECTIVE: We aimed to evaluate the predictive value of aspartate aminotransferase (AST)-to-platelet ratio index (APRI) for PNAC in infants with extremely low birth weight (ELBW, birth weight < 1000 g) infants. METHODS: We retrospectively reviewed the medical records of ELBW infants from March 2010 to February 2017. Clinical data and the serial APRI, AST, alanine aminotransferase (ALT), AST-to-ALT ratio, and direct bilirubin (DB) were analyzed. PNAC was diagnosed in infants with a history of PN for at least 2 weeks and direct bilirubin concentrations > 2 mg/dL after other causes of neonatal cholestasis were excluded. RESULTS: Among the 179 eligible ELBW infants, 56 (31.3%) were diagnosed with PNAC. APRI significantly differed between infants with PNAC and those without PNAC. The best APRI cut-off point was 0.410 at 2 weeks after the start of PN (area under the receiver operating characteristic curve = 0.752, p < 0.05; positive predictive value, 50.6%; negative predictive value, 84.1%). CONCLUSION: APRI at 2 weeks after PN could be a reliable predictor of PNAC development in ELBW infants on PN.

[Effects of different feeding patterns on the growth and development of infants with very/extremely low birth weight].

OBJECTIVE: To investigate the growth and development of very low birth weight (VLBW)/extremely low birth weight (ELBW) preterm infants within the corrected age of 6 months and the effect of different feeding patterns on growth and development. METHODS: A total of 109 VLBW/ELBW preterm infants who were discharged from January 2016 to April 2017 and who had completed regular follow-up were enrolled, and their growth and development within the corrected age of 6 months were monitored. The Z-score method was used to evaluate physical indices and analyze the effect of different feeding patterns (breastfeeding group: breast milk + human milk fortifier; mixed feeding group: breast milk + preterm formula milk; artificial feeding: preterm formula milk) on growth and development. RESULTS: The peaks of weight-for-age Z-score, height-for-age Z-score, weight-for-height Z-score, and BMI-for-age Z-score occurred within the corrected age of 3 months, and the peak of head circumference-for-age Z-score occurred at the corrected age of 5 months. Growth deviation of the infants often occurred within the corrected age of 1-3 months. At the corrected age of 3 months, the breastfeeding group had significantly better body weight, height and head circumference growth than the mixed feeding group and/or the artificial feeding group (P<0.05). At the corrected age of 6 months, the breastfeeding group had significantly better head circumference and body length growth than the mixed feeding group and/or the artificial feeding group (P<0.05). CONCLUSIONS: Growth deviation of VLBW/ELBW preterm infants often occurs within the corrected age of 1-3 months, suggesting that early individualized follow-up and nutritional guidance should be strengthened to reduce growth deviation. Maternal breastfeeding with the addition of human milk fortifier is the best feeding pattern for VLBW/ELBW preterm infants.

Effect of Dedicated Lactation Support Services on Breastfeeding Outcomes in Extremely-Low-Birth-Weight Neonates.

BACKGROUND: Breastfeeding is associated with major benefits for high-risk infants born prematurely, yet this population faces significant challenges to breastfeeding. Lactation services provide successful interventions, yet the impact of lactation services on breastfeeding outcomes in preterm infants is understudied. Research aim: The provision of full-time lactation support in the neonatal intensive care unit (NICU) will improve quantitative breastfeeding measures in premature infants. METHODS: A longitudinal retrospective nonexperimental design was used. Data were collected from medical records of breastfeeding outcomes in patients 30 weeks' gestational age and under admitted to a level IV regional NICU over three epochs of varying levels of lactation services, from none to full time. Demographic, medical, and breastfeeding data were collected. Data analysis was performed using standard statistical tests and hierarchical regression analysis. RESULTS: A significant increase in the number of lactation consults was observed across epochs, and the number of infants who received human milk via feeding at the breast, as the first oral feeding, increased across epochs. After controlling for covariates, the odds of infants receiving any human milk compared with exclusive formula feeding increased across epochs. CONCLUSION: The provision of full-time dedicated NICU lactation support is associated with an increase in breastfeeding outcome measures for high-risk preterm infants.

Linking extremely low birth weight and internalizing behaviors in adult survivors: Influences of neuroendocrine dysregulation.

Young adult survivors of extremely low birth weight (ELBW; <1000 g) are known to be at elevated risk for internalizing problems, though little is known about the mechanisms that may lead to higher levels of psychopathology in this vulnerable group. We examined the moderating influence of neuroendocrine functioning on the link between being born at ELBW and internalizing behaviors at age 30-35. Salivary cortisol was collected 20 min after completion of a social stress task in 83 ELBW adult survivors and 89 normal birth weight (NBW; >2500 g) controls. Using a median split, participants were separated into two groups (high or low afternoon cortisol levels). ELBW survivors with "high" afternoon cortisol levels self-reported significantly higher levels of internalizing behaviors compared to those with "low" afternoon cortisol levels. This association between afternoon cortisol and internalizing symptoms did not exist among NBW controls. These results are suggestive of a differential susceptibility for internalizing behaviors among ELBW survivors, depending on their ability to regulate neuroendocrine responses.

S100A12 and hBD2 correlate with the composition of the fecal microflora in ELBW infants and expansion of E. coli is associated with NEC.

OBJECTIVE: To describe the development of the gut microbiota in extremely low birth weight (ELBW) infants with and without necrotizing enterocolitis (NEC) between April 2008 and December 2009, fecal microflora was prospectively analyzed in fecal samples of all ELBW infants using real-time PCR assays. In addition, fecal inflammatory were measured. RESULTS: Fecal microflora established early in ELBW infants and microbiota composition remained stable over the first 28 days of life except for the prevalence of C. difficile which decreased with decreasing antibiotic use. Infants who subsequently developed NEC had an increase of total bacterial count (9.8-fold) 24 h prior to clinical symptoms mainly due to the expansion of E. coli species (21.6-fold), whereas microbiota composition did not differ from healthy ELBW infants five days before onset of NEC. Importantly, S100A12 and hBD2 positively correlated with the total and E. coli bacterial CFU/g feces (r (2) 0.4 and 0.64, resp.). CONCLUSIONS: In summary, we found evidence for a disturbed homeostasis between the intestinal microbiome and host immunity in ELBW infants with NEC. Moreover, S100A12 and hBD2 correlate with the fecal microbiota thus linking the intestinal innate immune response to the bacterial colonization thus possibly providing a diagnostic tool in the future.

Aggressive parenteral nutrition in sick very low birth weight babies: a randomized controlled trial.

Survival of preterm neonates in developing world has improved. Developing countries lag behind in nutritional management in NICU especially parenteral nutrition (PN). This randomized controlled trial was done to evaluate the effect of aggressive parenteral nutrition on nitrogen retention of sick VLBW and extremely low birth weight (ELBW) babies. From September 2009 to February 2010, total 34 babies were randomized to receive aggressive parenteral nutrition (APN)(n=17) or standard parenteral nutrition (SPN) (n=17). The average daily total and PN calory intake of babies in APN group was significantly higher during first week. APN was well-tolerated; however, nitrogen retention was not significantly higher in APN group. Aggressive parenteral nutrition in sick VLBW babies is feasible in developing world, though it did not improve nitrogen retention in first week of life.

Feeding extremely low birth weight infants.

CME EDUCATIONAL OBJECTIVES: 1.List the indications for parenteral nutrition in the preterm infant.2.Estimate protein and calories required by a preterm infant to support appropriate fetal weight gain.3.Discuss the calcium and phosphorus needs of preterm infants. The patient presented as a 5-week-old 26 week preterm infant, with a birth weight of 686 g. Her mother was 25 years old. The child's Apgar scores were 6 and 7 at 1 and 5 minutes. The infant was intubated after birth and placed on the high-frequency oscillator on day of life (DOL) 3 because of worsening respiratory failure. She was placed back on conventional mechanical ventilation on DOL 7, extubated on DOL 15, and placed on 40% oxygen via nasal cannula. She was discharged home on DOL 84 without mechanical ventilation.

Cerebral and somatic rSO2 in sick preterm infants.

Near infrared spectroscopy (NIRS) measures the regional tissue oxygen saturation (rSO2) of various organs and provides a reflection of the balance between tissue oxygen supply and demand. Oxymetry assessed via NIRS has been proposed as a 'standard of care' and today it is already widely used in the NICU. This approach allows detection of any acute change in cerebral haemodynamics and continuous monitoring of cerebral and somatic oxygenation. This work describes three clinical cases of preterm VLBW infants which showed special points of interest during both cerebral and somatic NIRS monitoring.

Hypophosphatemia in small for gestational age extremely low birth weight infants receiving parenteral nutrition in the first week after birth.

OBJECTIVES: To investigate the risk of hypophosphatemia and hypercalcemia in small for gestational age (SGA) extremely low birth weight infants (ELBWI) receiving parenteral nutrition. METHODS: A retrospective review of 58 ELBWI was conducted. Serum calcium (Ca) and phosphate (PO4) concentrations on days 1 and 8 after birth were examined for associations with body measurements and nutritional factors in the 1st week of life. RESULTS: Lower birth weight standard deviation (SD) scores were correlated with hypophosphatemia and hypercalcemia in SGA ELBWI on day 8. Higher parenteral amino acid (AA) administration was correlated with hypophosphatemia on day 8. SGA ELBWI exhibited lower serum PO4 concentrations compared to appropriate for gestational age (AGA) ELBWI on day 8. CONCLUSIONS: This is the 1st study to report that parenteral nutrition, in the first 7 days after birth for the treatment of SGA ELBWI, was correlated with hypophosphatemia and hypercalcemia. It is important to determine an ideal nutrition protocol for treatment of SGA ELBWI.

Clinical metabolomics and urinary NGAL for the early prediction of chronic kidney disease in healthy adults born ELBW.

BACKGROUND: Clinical metabolomics is a recent "omic" technology which is defined as a global holistic overview of the personal metabolic status (fingerprinting). This technique allows to prove metabolic differences in different groups of people with the opportunity to explore interactions such as genotype-phenotype and genotype-environment type, whether normal or pathological. AIM: To study chronic kidney injury 1) using urine metabolomic profiles of young adults born extremely low-birth weight (ELBW) and 2) correlating a biomarker of kidney injury, urinary neutrophil gelatinase-associated lipocalin (NGAL), in order to confirm the metabolomic injury profile. METHOD: Urine samples were collected from a group of 18 people (mean: 24-year-old, std: 4.27) who were born with ELBW and a group of 13 who were born at term appropriate for gestational age (AGA) as control (mean 25-year-old, std: 5.15). Urine samples were analyzed by (1)H-nuclear magnetic resonance spectroscopy, and then submitted to unsupervised and supervised multivariate analysis. Urine NGAL (uNGAL) was measured using ARCHITECT (ABBOTT diagnostic NGAL kit). RESULTS: With a multivariate approach and using a supervised analysis method, PLS-DA, (partial least squares discriminant analysis) we could correlate ELBW metabolic profiles with uNGAL concentration. Conversely, uNGAL could not be correlated to AGA. CONCLUSIONS: This study demonstrates the relevance of the metabolomic technique as a predictive tool of the metabolic status of exELBW. This was confirmed by the use of uNGAL as a biomarker which may predict a subclinical pathological process in the kidney such as chronic kidney disease.

Results of extremely-low-birth-weight infants randomized to receive extra enteral calcium supply.

BACKGROUND AND OBJECTIVE: Bone mineral deficiency continues to occur in extremely-low-birth-weight (ELBW) infants despite formulas enriched in calcium (Ca) and phosphorus (P). This study tested whether extra enteral Ca supplementation increases bone mineral content (BMC) and prevents dolichocephalic head flattening and myopia in ELBW infants. STUDY DESIGN: Infants 401 to 1000 birth weight receiving enteral feeds were randomized to receive feeds supplemented with Ca-gluconate powder or pure standard feeds. The main outcome measures were the excretion of Ca and P by weekly spot urine measurements, the degree of dolichocephalic deformation (fronto-occipital diameter to biparietal diameter ratio, FOD/BPD) at 36 weeks postmenstrual age, and the BMC (by dual-energy x-ray absorptiometry) at discharge. Cycloplegic refraction was measured at 18 to 22 months corrected age. PATIENTS AND RESULTS: Ninety-nine ELBW infants with a gestational age of 26 weeks (23-31) (median [minimum-maximum]) were randomized at a postnatal age of 12 days (5-23) weighing 790 g (440-1700). Urinary Ca excretion increased and P excretion decreased in the Ca-supplemented group. Total BMC was 89.9 ± 2.4 g (mean ±â€ŠSE) in the supplemented group and 85.2 ± 2.6 g in the control group (P = 0.19). The FOD/BPD was 1.50 (1.13-1.69, mean ± SD [standard deviation]) and 1.47 (1.18-1.64) in the supplemented and control groups, and the refraction 0.98  ± 1.23 and 1.40 ± 1.33 dpt (P = 0.68), respectively in 64 ELBW infants (79% of survivors) at 2-year follow-up. CONCLUSIONS: Extra enteral Ca supplementation did not change BMC, head shape, or refraction. The decreased P excretion may reflect P deficiency in infants receiving extra Ca, preventing improved bone mineral accretion.

Parenteral nutrition--ascites with acute renal failure as a complication from an umbilical venous catheter in an extremely low birth weight infant.

Umbilical venous catheters (UVCs) are frequently used in the neonatal intensive care setting and play a crucial role in the management of extremely low birth weight (ELBW) infants. One very rare complication reported is parenteral nutrition (PN) ascites secondary to vessel perforation or hepatic erosion by PN at the tip of malpositioned UVCs with various hepatic lesions. We describe a case of early onset PN ascites with no obvious associated hepatic lesion but complicated by pre-renal acute renal failure in an ELBW infant with the tip positioned between the 10th and 11th thoracic vertebrae.

In search of the optimal oxygen saturation for extremely low birth weight infants: a systematic review and meta-analysis.

BACKGROUND: The optimal arterial oxygen saturation in the first weeks of life is unknown for immature newborn infants. OBJECTIVES: To determine the effect of targeting high versus low oxygen saturation in the first weeks of life on the outcome of very low and extremely low birth weight infants. METHODS: Randomized and observational studies were sought that compared the outcomes in babies with high or low oxygen saturation targeting assessed by pulse oximetry. RESULTS: Ten studies were identified, of which 8 had severe retinopathy of prematurity (n = 3811) and 8 had bronchopulmonary dysplasia/lung problems (n = 4612) as outcomes. Two studies also provided survival data. The relative risk (RR) in favor of low SpO2 was 0.42 (95% CI 0.34-0.51) for severe retinopathy of prematurity, 0.73 (95% CI 0.63-0.86) for bronchopulmonary dysplasia/lung problems, and 1.12 (95% CI 0.86-1.45) for mortality. There was 1 randomized trial with retinopathy of prematurity, 3 with bronchopulmonary dysplasia/lung problems, and 1 with mortality as the outcome. When analyzing the randomized trial separately, the RR (95% CI) for severe retinopathy of prematurity was 0.48 (0.34-0.68), for bronchopulmonary dyslasia/lung problems it was 0.79 (0.64-0.97), and for mortality it was 1.27 (1.01-1.60). CONCLUSIONS: A low oxygen saturation approach reduces severe retinopathy of prematurity by 50%, i.e., from 20.9 to 9.5%, and bronchopulmonary dysplasia/lung problems by 25%, i.e., from 40.8 to 29.7%. Further randomized trials are needed to provide definite conclusions and to assess whether reducing oxygen saturation has an impact on mortality among very and extremely low birth weight infants.

Pharmacokinetics, safety, and biologic effects of azithromycin in extremely preterm infants at risk for ureaplasma colonization and bronchopulmonary dysplasia.

Ureaplasma spp. respiratory tract colonization is a significant risk factor for bronchopulmonary dysplasia (BPD), a chronic lung disorder in preterm infants. As an initial step preparatory to future clinical trials to evaluate the clinical efficacy of azithromycin to prevent BPD, the authors characterized the pharmacokinetics, safety, and biological effects of a single intravenous dose of azithromycin (10 mg/kg) in preterm neonates (n = 12) 24 to 28 weeks gestation at risk for Ureaplasma infection and BPD. A 2-compartment structural model with the clearance and volume of peripheral compartment (V2) allometrically scaled on body weight (WT) best described the pharmacokinetics of azithromycin in preterm neonates. The estimated parameters were clearance [0.18 L/h × WT(kg)(0.75)], intercompartmental clearance [1.0 L/h], volume of distribution of central compartment [0.93 L], and V2 [14.2 L × WT(kg)]. There were no serious adverse events attributed to azithromycin. A single dose of azithromycin did not suppress inflammatory cytokines or myeloperoxidase activity in tracheal aspirates. These results demonstrated the safety of azithromycin and developed a pharmacokinetic model that is useful for future simulation-based clinical trials for eradicating Ureaplasma and preventing BPD in preterm neonates.