Early diagnostic value of C-reactive protein as an inflammatory marker for moderate-to-severe bronchopulmonary dysplasia in premature infants with birth weight less than 1500 g.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a serious respiratory complication in premature infants and moderate-to-severe BPD may affect the long-term quality of life and lack of specific treatment once it happened. Therefore, it is necessary to identify early diagnostic biomarkers for moderate-to-severe BPD. METHODS: This retrospective cohort study included all premature infants with birth weight <1500 g from March 1, 2015 to June 30, 2017. Patients were categorized into mild BPD, moderate-to-severe BPD and non BPD groups. Data collected included patient characteristics, C-reactive protein (CRP) tested at six time points, including 1d (2 h after birth and before the first feeding), 3d, 7d, 2w, 3w, and 4w after birth, and maternal factors. Ordinal regression analysis was used to identify independent predictors of moderate-to-severe BPD and receiver operating characteristic (ROC) curve was used to evaluate the value of CRP as an early diagnostic marker for moderate-to-severe BPD. RESULTS: A total of 831 patients were recruited. BPD occurred in 156/831 premature infants with birth weight less than 1500 g. Lower birth weight (OR = 0.998, 95% CI 0.997-0.999, P = 0.004), higher CRP level 3 days after birth (OR = 1.287, 95% CI 1.195-1.384, P = 0.000), and hemodynamically significant patent ductus arteriosus (HsPDA) (OR = 12.256, 95% CI 3.766-39.845, P = 0.000) were independent risk factors for moderate-to-severe BPD. The area under curve of the CRP level 3 days after birth for diagnosing moderate-to-severe BPD was 0.867 (95% CI, 0.823-0.912, P = 0.000). The sensitivity was 83.0% and the specificity was 78.3% when the cut-off value was set at 4.105 mg/L. CONCLUSION: The CRP level 3 days after birth may be used as an early diagnostic marker for moderate-to-severe BPD in preterm infants who have the risk factors for BPD with birth weight less than 1500 g.

A clinical study on plasma biomarkers for deciding the use of adjuvant corticosteroid therapy in bronchopulmonary dysplasia of premature infants.

Objective: The study was designed to investigate some plasma markers which help us to decide the use of adjuvant corticosteroid therapy in bronchopulmonary dysplasia (BPD) of premature infants. Methods: Thirty BPD infants were treated by dexamethasone. Among these cases, dexamethasone was significant effective in 10 cases, and no significant effective in 20 cases. These patients were divided into two groups as the significant effect (SE) group (n=10) and the non-significant effect (NE) group (n=20) according to the curative effect of dexamethasone. Fifteen non-BPD infants with gestational age and gender matching were selected as the control group. Plasma samples before and after dexamethasone treatment were collected from three infants chosen randomly from SEG for the data-independent acquisition (DIA) analysis. ELISA was further used to detect the levels of differential proteins LRP1 and S100A8 in all individuals, including SE, NE and control groups. Results: DIA analysis results showed that after dexamethasone treatment, there were a total of 52 plasma proteins that showed significant differences, of which 43 proteins were down-regulated and 9 proteins were up-regulated. LRP1 and S100A8 were two plasma proteins that were significantly changed after dexamethasone treatment. Compared with the control group, plasma LRP1 was significantly increased in BPD. Interestingly, the plasma concentration of LRP1 in the NE group was significantly higher than that in the SE group. S100A8, as an indicator of plasma inflammation, was significantly higher in BPD than the control group. Unlike LRP1, there was no significantly difference between the SE and NE group (P=0.279) before dexamethasone treatment. Conclusion: Elevated plasma LRP1 and S100A8 in BPD infants are two indicators that correlated with the efficacy of dexamethasone, and might be used as biomarkers for deciding the use of adjuvant corticosteroids therapy in the BPD.

Interleukin 8 may predict surgical necrotizing enterocolitis in infants born less than 1500 g.

Necrotizing enterocolitis (NEC) often leads to gastrointestinal emergency resulting high mortality in very low birth weight infants (VLBWIs) requiring surgery. To date, few studies have explored the role of serum cytokines in the development of feeding intolerance (FI) or NEC outcomes in VLBWIs. Infants born weighing <1500 g or of 32 weeks of gestational age were prospectively enrolled from May 2018 to Dec 2019. We measured several cytokines routinely within 72 h of life, even before NEC-like symptoms developed. NEC or FI group comprised 17 (27.4%) infants, and 6 (9.7%) infants had surgical NEC. The gestational age and birth weight were significantly lower in the NEC or FI group with more prematurity-related complications. The surgical NEC group also demonstrated significantly lower gestational age and birth weight along with more infants experiencing refractory hypotension within a 1 week of life, pulmonary hypertension, and patent ductus arteriosus. IL-10 levels were significantly higher in the NEC or FI group, whereas IL-8 levels were significantly higher in the infants with surgical NEC. Our findings indicated to IL-8 can predict surgical NEC while increased IL-10 can predict NEC development in VLBWIs.

The association of γδ-T cells with bronchopulmonary dysplasia in premature infants.

BACKGROUND: As the survival rate of premature infants increases, the incidence of bronchopulmonary dysplasia (BPD), a chronic complication of premature infants, is also higher than before. The pathogenesis of BPD is complicated, and immune imbalance and inflammatory response may play important roles in it. OBJECTIVE: To investigate the correlation between lymphocyte subsets in peripheral blood, especially γδ-T cells, and BPD of preterm infants. MATERIALS AND METHOD: The study was carried out with the peripheral blood of premature infants (GA < 32 weeks, BW < 1500 g), which were collected at 24 h or 3-4 weeks after birth. The infants were divided into non-BPD groups and BPD groups that were classified as mild or moderate and severe in preterm infants based on the magnitude of respiratory support at 28 days age and 36 weeks postmenstrual age. The γδ-T, CD3+, CD4+, CD8+ and total lymphocyte subsets in peripheral blood were detected by flow cytometry. RESULTS: The percentages of T lymphocyte subsets in peripheral blood were not different between BPD and non-BPD within 24 h after birth. And no significant difference was found in T lymphocyte subsets among neonates with BPD of different severities. However, the infants who developed BPD had a significant increase in γδ-T cells compared to non-BPD ones within 3-4 weeks after birth. CONCLUSIONS: It seems that γδ-T cells in peripheral blood are correlated with BPD. However, the causality of BPD and various lymphocytes remains unclear, which need to be further studied.

Survey on clinical use and non-use of recombinant human erythropoietin in European neonatal units.

Objectives Recombinant human erythropoietin (rhEPO) has been shown to effectively and safely prevent the anemia of prematurity and to reduce the transfusion need in very low birth weight (VLBW) infants and has been licensed for this indication in Europe in 1997. The objective of the study was to obtain information on the use or non-use of rhEPO in neonatal units in Germany and other European countries. Methods Anonymized 14-questions web-based questionnaire. Results Seventy-nine questionnaires from Germany and 63 questionnaires from other 15 European countries were completed. Of the responders, 39% indicated to use rhEPO routinely or occasionally in VLBW infants, whereas 61% responded to never use rhEPO in this population. The major reasons given for non-use were lack of recommendation in national guidelines (69%) and/or doubt about efficacy of rhEPO to reduce transfusion need (53%). Twenty-seven percent of the responders indicated to use rhEPO for neonates with birth weights above 1,500 g. Neuroprotection in VLBW infants (26%) and hypoxic ischemic encephalopathy in term neonates (27%) were given as indications for off label use of rhEPO. Conclusions This survey indicates that rhEPO is used for the anemia of prematurity as licensed in less than half of neonatal units in Germany and other European countries. On the other hand it seems to be used off label in neonates for neuroprotection in a considerable number of units although there is no final evidence on its neuroprotective effects.

The Course Of IGF-1 Levels and Nutrient Intake in Extremely and Very Preterm Infants During Hospitalisation.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) plays an important role in the complex association between nutrition, growth, and maturation in extremely and very preterm infants. Nevertheless, in this population, research on associations between IGF-1 and nutrition is limited. Therefore this study aimed to evaluate the possible associations between the course of IGF-1 levels and nutrient intake between preterm birth and 36 weeks postmenstrual age (PMA). METHODS: 87 infants born between 24 and 32 weeks gestational age were followed up to 36 weeks PMA. Actual daily macronutrient intake was calculated, and growth was assessed weekly. IGF-1 was sampled from umbilical cord blood at birth and every other week thereafter. RESULTS: There was an inverse relationship between the amount of parenteral nutrition in the second week of life and IGF-1. Total protein, fat, and carbohydrate intake, as well as total energy intake, primarily showed a positive association with IGF-1 levels, particularly between 30 and 33 weeks PMA. Gestational age, bronchopulmonary dysplasia (BPD), and weight were significant confounders in the association between nutrient intake and IGF-1 levels. CONCLUSION: Parenteral nutrition was found to be a negative predictor of IGF-1 levels, and there could potentially be a time frame in which macronutrient intake is unable to impact IGF-1 levels. Future research should aim to narrow down this time frame and to gain more insight into factors enhancing or decreasing the response of IGF-1 to nutrition, e.g., age and inflammatory state, to align nutritional interventions accordingly.

Outcomes after implementing restrictive blood transfusion criteria in extremely premature infants.

OBJECTIVE: To assess mortality and morbidities in very low birthweight (VLBW) infants before and after changing to a restrictive blood transfusion guideline (RTG). STUDY DESIGN: This is a large retrospective study comparing outcomes of a liberal transfusion guideline (LTG) and RTG in VLBW infants admitted to a large single neonatal intensive care unit. Blood and platelet transfusion details, mortality, and diagnoses of frequently diagnosed morbidities were collected for each infant. RESULTS: Mortality was similar between RTG and LTG groups (6.8% vs. 6.3%, p = 0.755). Rates of periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), sepsis and the diagnosis of necrotizing enterocolitis (NEC) within 48 h of a PRBC transfusion were significantly lower with RTG (p < 0.05). Chronic lung disease was similar between groups. CONCLUSION: RTG are safe compared to LTG, and are associated with lower rates of PVL, ROP, transfusion-associated cases of NEC and sepsis.

Nucleated red blood cells and serum lactate values on days 2 and 5 are associated with mortality and morbidity in VLBW infants.

AIM: To correlate nucleated red blood cell counts and serum lactate concentrations on day 2 and 5 of life with morbidity and mortality in very low birth weight infants and to determine corresponding cutoff values. METHODS: Retrospective analysis in a cohort of very low birth weight infants. RESULTS: 250 very low birth weight infants were included in this study. Gestational age ranged from 23 to 35 weeks (mean 29.04) and birth weight was 320-1500 g (mean 1047.9). 55 (22%) patients developed intraventricular hemorrhage, 55 (22%) bronchopulmonary dysplasia, 12 (4.8%) periventricular leukomalacia, 93 (37.2%) retinopathy of prematurity, and 1 (0.4%) necrotizing enterocolitis. Mortality rate was 25/250 (10%). Nucleated red blood cells and serum lactate on day 2 of life were associated with mortality (p < 0.001). Serum lactate on day 5 of life demonstrated an association with retinopathy of prematurity (p = 0.017), bronchopulmonary dysplasia (p = 0.044), and intraventricular hemorrhage (p < 0.001). Cutoff values predicting mortality were >89.5 nucleated red blood cells/100 leucocytes (sensitivity 68.2%, specificity 89.0%) and serum lactate concentrations >8.5 mmol/l (sensitivity 69.6%, specificity 93.5%) on day 2 of life. CONCLUSION: We conclude that both nucleated red blood cell count and serum lactate concentration are valuable biomarkers in predicting important outcome parameters in very low birth weight infants.

Effect of increased enteral protein intake on plasma and urinary urea concentrations in preterm infants born at < 32 weeks gestation and < 1500 g birth weight enrolled in a randomized controlled trial - a secondary analysis.

BACKGROUND: Feeding breast milk is associated with reduced morbidity and mortality, as well as improved neurodevelopmental outcome but does not meet the high nutritional requirements of preterm infants. Both plasma and urinary urea concentrations represent amino acid oxidation and low concentrations may indicate insufficient protein supply. This study assesses the effect of different levels of enteral protein on plasma and urinary urea concentrations and determines if the urinary urea-creatinine ratio provides reliable information about the protein status of preterm infants. METHODS: Sixty preterm infants (birthweight < 1500 g; gestational age < 32 weeks) were enrolled in a randomized controlled trial and assigned to either a lower-protein group (median protein intake 3.7 g/kg/d) or a higher-protein group (median protein intake 4,3 g/kg/d). Half the patients in the higher-protein group received standardized supplementation with a supplement adding 1.8 g protein/100 ml milk, the other half received individual supplementation depending on the respective mother's milk macronutrient content. Plasma urea concentration was determined in two scheduled blood samples (BS1; BS2); urinary urea and creatinine concentrations in weekly spot urine samples. RESULTS: The higher-protein group showed higher plasma urea concentrations in both BS1 and BS2 and a higher urinary urea-creatinine-ratio in week 3 and 5-7 compared to the lower-protein group. In addition, a highly positive correlation between plasma urea concentrations and the urinary urea-creatinine-ratio (p < 0.0001) and between actual protein intake and plasma urea concentrations and the urinary urea-creatinine-ratio (both p < 0.0001) was shown. CONCLUSIONS: The urinary urea-creatinine-ratio, just like plasma urea concentrations, may help to estimate actual protein supply, absorption and oxidation in preterm infants and, additionally, can be determined non-invasively. Further investigations are needed to determine reliable cut-off values of urinary urea concentrations to ensure appropriate protein intake. TRIAL REGISTRATION: Clinicaltrials.gov; NCT01773902 registered 15 January 2013, retrospectively registered.

Half-life of plasma phytosterols in very low birth weight preterm infants on routine parenteral nutrition with vegetable oil-based lipid emulsions.

BACKGROUND: Phytosterols in vegetable oil (VO)-based lipid emulsions (LE) likely contribute to parenteral nutrition-associated cholestasis (PNAC) in preterm infants. No characterization of plasma phytosterol half-lives has been done in very low birth weight (VLBW) preterm infants receiving parenteral nutrition (PN) with LE. METHODS: In a prospective cohort study, 45 VLBW preterm infants who received PN underwent serial blood sample measurements of sitosterol (SITO), campesterol (CAMP), and stigmasterol (STIGM). Plasma phytosterol half-lives were calculated from the phytosterol concentrations-decay curves by using a single-compartment model. RESULTS: After the stop of the intravenous LE, study infants had significantly lower plasma total CAMP, STIGM and SITO concentrations. The decay of plasma phytosterol concentrations was monoexponential. Half-life of plasma total CAMP, STIGM and SITO was 13.5 ± 6.9, 10.3 ± 4.5 and 10.3 ± 4.0 days, respectively. Plasma phytosterol half-lives did not correlate with gestational age, birth weight, cumulative phytosterol intakes and plasma conjugated bilirubin. CONCLUSION: VLBW preterm infants on PN with LE had rather long plasma phytosterol half-lives similar to hypercholesterolemic adults and phytosterolemic homozygotes patients. We speculate that the accumulation of phytosterols could contribute to their vulnerability to PNAC. CLINICAL TRIAL REGISTRY: The Ethics Committee of Marche-Italy (DG/469); www.clinicaltrials.gov (identification number NCT02758834).

Reference values for serum cystatin C in very low-birthweight infants: From two centres of China.

AIM: To determine the level of cystatin C (Cys-C) values in preterm babies for the purpose of becoming a good endogenous marker of renal function. METHODS: A total of 366 very low-birthweight infants (including 70 extremely low-birthweight babies) with gestational age <37 weeks born in two centres were studied. RESULTS: In very low-birthweight infants, the mean level of Cys-C was 1.96 ± 0.44 mg/L in blood samples taken on day 1, 1.78 ± 0.49 mg/L on day 7 and 1.71 ± 0.47 mg/L on day 28. In extremely low-birthweight infants, the mean level of Cys-C was 2.00 ± 0.49 mg/L on day 1, 1.63 ± 0.38 mg/L on day 7 and 1.62 ± 0.55 mg/L on day 28, respectively. Compared to serum creatinine and blood urea nitrogen, Cys-C level was independent of birthweight and gestational age. CONCLUSION: Cys-C is regarded as an alternative for assessing renal function in very low-birthweight infants, but its advantages over serum creatinine and blood urea nitrogen has not been fully proved yet. Hence, larger sample study is still necessary.

Acute kidney injury in premature newborns-definition, etiology, and outcome.

BACKGROUND: Neonatal acute kidney injury (AKI) is common and is associated with poor outcomes. New criteria for the diagnosis of AKI were introduced based on the increase in serum creatinine (SCr) levels and/or reduction of urine output (UOP). Yet, there is no generally accepted opinion so far, which criteria (whether SCr, UOP, or their combination) are the most appropriate to diagnose neonatal AKI. METHODS: The retrospective study included 195 prematurely born neonates who fulfilled all inclusion criteria (with at least two SCr measurements). In all the neonates included in the study, AKI was diagnosed using three different definitions: (1) SCr criteria (an increase in SCr values of ≥0.3 mg/dl), (2) UOP criteria (UOP < 1.5 ml/kg/h), and (3) SCr + UOP criteria. RESULTS: Out of all of the patients the study included, 85 (44%) were diagnosed with AKI. The neonates who had AKI had a significantly lower gestational age, birth weight, and Apgar score, longer duration of mechanical ventilation, and a higher mortality rate. SCr + UOP criteria showed higher sensitivity for prediction of death compared to SCr or UOP alone (p = 0.0008, 95% CI 0.040-0.154, and p = 0.0038, 95% CI 0.024-0.125, respectively). If only SCr or only UOP criterion are used, they fail to identify AKI in 61 and 67%, respectively. AKI was an independent risk factor for death (OR 7.4875; CI 3.1887-17.5816). CONCLUSIONS: Similar to other studies, our data showed that neonates with AKI have worse outcome. Neonatal AKI defined based on SCr + UOP criteria is a better predictor of death than neonatal AKI defined based only on the SCr or UOP criteria. Also, by using SCr + UOP criteria for diagnosing neonatal AKI, more patients with AKI are recruited than when only one of those criteria is used.

Increased urinary neutrophil gelatinase-associated lipocalin in very-low-birth-weight infants with oliguria and normal serum creatinine.

BACKGROUND: In infants, oliguria is defined as a urine output of <1.5 mL/kg/h. The aim of our study was to assess the impact of oliguria on urinary neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (CysC) levels in very-low-birth-weight infants (VLBWIs) with a normal serum creatinine (Cr) level. METHODS: Fifty-seven VLBWIs were enrolled in the study. Urinary NGAL, serum CysC and Cr levels and urinary NGAL/Cr ratios were measured. Infants with Apgar scores of >5 at 5 min and/or a serum Cr level of >1.5 mg/dL or those treated for patent ductus arteriosus were excluded. In case of antibiotic treatment, blood and urine samples were collected at ≥48 h after discontinuation of antibiotic treatment. RESULTS: There was a significant difference in gestational age between infants with oliguric episodes during hospitalization and those without, but not in birth weight, perinatal or postnatal factors. Gestational age was negatively correlated with urinary NGAL and serum CysC levels and urinary NGAL/Cr ratio (p < 0.05), whereas postnatal age was negatively correlated with serum Cr level and urinary NGAL/Cr ratio (p < 0.05). Of the 117 urine and blood samples collected, 25 (21.4%) were obtained from neonates with oliguric episodes. After adjusting for gestational age and postnatal age, comparison of samples collected in infants with and without oliguric episodes revealed significant differences in the mean level of urinary NGAL and in the urinary NGAL/Cr ratio, but not in mean serum CysC or serum Cr levels. The urinary NGAL level [area under the curve (AUC) 0.886, 95% confidence interval (CI) 0.814-0.937] and urinary NGAL/Cr ratio (AUC 0.853, 95% CI 0.775-0.911) showed significantly greater discrimination for oliguria than serum CysC (AUC 0.610, 95% CI: 0.515-0.699) or serum Cr (AUC 0.747, 95%CI 0.659-0.823) levels. CONCLUSIONS: Urinary NGAL level and urinary NGAL/Cr ratio were more sensitive markers for the presence of oliguria in VLBWIs with normal serum Cr levels than serum CysC level.

Biomarkers of adiposity are elevated in preterm very-low-birth-weight infants at 1, 2, and 3 y of age.

BACKGROUND: Preterm, very-low-birth-weight (PT-VLBW) neonates are at-risk for metabolic syndrome later in life. At 1-3 y, they exhibit excessive weight-for-length z-scores (Wt-LZ) and elevated systolic blood pressures (SBP). Serum adipokines are biomarkers of adiposity, but expression in PT-VLBW infants is unclear. We examined the correlation between serum adipokine levels, anthropometric measures and SBP in PT-VLBW neonates at follow-up. METHODS: This was a cross-sectional cohort study of PT-VLBW infants at 1, 2, and 3 y of age (40/cohort). We measured SBP, abdominal circumference (AC) and anthropometrics; calculated age/gender-specific z-scores for Wt, L, Wt-L and subscapular skin fold (SSZ), and measured serum adipokines. RESULTS: Serum leptin was unaffected by chronologic age and gender, but was positively correlated with weight, Wt-LZ, AC, and SSZ at 1 and 3 y (P < 0.01). Female infants at 1 and 3 y had a more significant relationship than males between serum leptin and SSZ (P < 0.001, R = 0.75 and P < 0.001, R = 0.70, respectively). Adiponectin levels were 16-20% lower at 3 vs. 1-2 y (P = 0.02, ANOVA) and negatively correlated with SBP. CONCLUSION: Although serum leptin was unrelated to advancing age, gender, and SBP in PT-VLBW infants, levels correlated with measures of adiposity at 1 and 3 y, females > males, suggesting leptin resistance may occur in early infancy.

An Elevation of Serum Ferritin Level Might Increase Clinical Risk for the Persistence of Patent Ductus Arteriosus, Sepsis and Bronchopulmonary Dysplasia in Erythropoietin-Treated Very-Low-Birth-Weight Infants.

BACKGROUND: The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants. OBJECTIVE: The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs). METHODS: This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml. RESULTS: Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia. CONCLUSIONS: Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection.

The iron status at birth of neonates with risk factors for developing iron deficiency: a pilot study.

OBJECTIVE: Small-for-gestational-age (SGA) neonates, infants of diabetic mothers (IDM) and very-low-birth weight premature neonates (VLBW) are reported to have increased risk for developing iron deficiency and possibly associated neurocognitive delays. STUDY DESIGN: We conducted a pilot study to assess iron status at birth in at-risk neonates by measuring iron parameters in umbilical cord blood from SGA, IDM, VLBW and comparison neonates. RESULTS: Six of the 50 infants studied had biochemical evidence of iron deficiency at birth. Laboratory findings consistent with iron deficiency were found in one SGA, one IDM, three VLBW, and one comparison infant. None of the infants had evidence of iron deficiency anemia. CONCLUSIONS: Evidence of biochemical iron deficiency at birth was found in 17% of screened neonates. Studies are needed to determine whether these infants are at risk for developing iron-limited erythropoiesis, iron deficiency anemia or iron-deficient neurocognitive delay.

Acute Kidney Injury Urine Biomarkers in Very Low-Birth-Weight Infants.

BACKGROUND AND OBJECTIVES: Serum creatinine (SCr)-based AKI definitions have important limitations, particularly in very low-birth-weight (VLBW) neonates. Urine biomarkers may improve our ability to detect kidney damage. We assessed the association between 14 different urine biomarkers and AKI in VLBW infants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a prospective cohort study on 113 VLBW infants (weight ≤1200 g or <31 weeks' gestation) admitted to a regional neonatal intensive care unit at the University of Alabama at Birmingham between February 2012 and June 2013. SCr was measured on postnatal days 1, 2, 3, and 4 and was combined with clinically measured SCr to determine AKI according to Kidney Disease Improving Global Outcomes AKI definition (increase in SCr ≥0.3 mg/dl or ≥50% increase from previous lowest value). Urine was collected on the first 4 days (average number of urine collections, 3; range, 1-4). The maximum urine biomarkers and urine biomarker/creatinine levels were calculated for 12 urine biomarkers, and the minimum urine biomarker and biomarker/creatinine levels were assessed for two urine biomarkers. We compared these values between infants with and those without AKI. Ideal cutoffs, area under the receiver-operating characteristic curve , and area under the curve adjusted for gestational age were calculated. RESULTS: Cumulative incidence of AKI during the first 2 postnatal weeks was 28 of 113 (25%). Infants with AKI had higher maximum levels of urine cystatin C, neutrophil gelatinase-associated lipocalin, osteopontin, clusterin, and α glutathione S-transferase (2.0, 1.8, 1.7, 1.7, and 3.7 times higher, respectively) than infants without AKI. In addition, infants with AKI had lower minimum levels of epithelial growth factor and uromodulin than those without AKI (1.4 and 1.6 times lower, respectively). Most but not all participants had their maximum (or minimum) biomarker values preceding AKI. These associations remained after adjustment for gestational age. CONCLUSIONS: Urine biomarkers measured in the first 4 days of life are associated with AKI during the first postnatal weeks. Further evaluations are necessary to determine whether these biomarkers can predict important clinical outcomes. In addition, intervention studies that use biomarkers to stratify enrollment groups are needed before bedside evaluations can be incorporated into care.

Vitamin D and bronchopulmonary dysplasia in preterm infants.

OBJECTIVE: Vitamin D deficiency is associated with asthma and reactive airway disease in childhood but its potential contribution to bronchopulmonary dysplasia (BPD) in preterm infants is unknown. Preterm infants have lower levels of 25-hydroxyvitamin D (25(OH)D) at birth and are at risk for nutritional deficiencies after birth. The objective of the study was to evaluate the association of 25(OH)D concentrations at birth and at 36 weeks' corrected gestational age with BPD in preterm infants born before 29 completed weeks of gestation. STUDY DESIGN: We collected umbilical cord blood samples from 44 preterm infants (gestational age <29 weeks) delivered at Brigham and Women's Hospital in Boston. In addition, with parental consent we collected venous samples at 36 weeks' corrected age from 20 preterm infants born before 29 weeks' gestation (including 6 infants with previously collected cord blood). Samples were frozen at -80 °C until subsequent measurement of 25(OH)D levels by chemiluminescence. We used multivariable logistic models to adjust for gestational age and considered other confounding variables, including maternal race, age, mode of delivery and infant sex. RESULTS: Among 44 infants, 41 (93.2%) survived and 3 (6.8%) died before 36 weeks' corrected age. Median 25(OH)D levels at birth were 30.4 ng ml(-1) in preterm infants who subsequently died or developed BPD and 33.8 ng ml(-1) in infants who survived without BPD (P=0.6). Median 25(OH)D levels at corrected age of 36 weeks were 59.0 ng ml(-1) among survivors without BPD and 64.2 ng ml(-1) among survivors with BPD (P=0.9). Neither cord blood nor 36 weeks' corrected 25(OH)D levels were associated with odds of death or BPD (adjusted odds ratio (OR) 1.00, 95% confidence interval (CI): 0.73 to 1.37; and OR 0.93, 95% CI: 0.61 to 1.43, respectively). CONCLUSIONS: Among this population of extremely preterm infants neither cord blood nor the 36 weeks' corrected age 25(OH)D levels were associated with development of BPD. Notably, at the current level of supplementation, all extremely preterm infants in our cohort had achieved 25(OH)D levels >30 ng ml(-1) by 36 weeks' corrected age, which is thought to represent sufficiency in adult and pediatric populations.

Increasing F2-isoprostanes in the first month after birth predicts poor respiratory and neurodevelopmental outcomes in very preterm infants.

OBJECTIVE: This study examined the association between increased early oxidative stress, measured by F2-isoprostanes (IsoPs), and respiratory morbidity at term equivalent age and neurological impairment at 12 months of corrected age (CA). STUDY DESIGN: Plasma samples were collected from 136 premature infants on days 14 and 28 after birth. All participants were infants born at ⩽28 weeks of gestational age enrolled into the Prematurity and Respiratory Outcomes Program (PROP) study. Respiratory morbidity was determined at 40 weeks of postmenstrual age (PMA) by the Respiratory Severity Index (RSI), a composite measure of oxygen and pressure support. Neurodevelopmental assessment was performed using the Developmental Assessment of Young Children (DAYC) at 12 months of CA. Multivariable logistic regression models estimated associations between IsoP change, RSI and DAYC scores. Mediation analysis was performed to determine the relationship between IsoPs and later outcomes. RESULTS: Developmental data were available for 121 patients (90% of enrolled) at 12 months. For each 50-unit increase in IsoPs, regression modeling predicted decreases in cognitive, communication and motor scores of -1.9, -1.2 and -2.4 points, respectively (P<0.001). IsoP increase was also associated with increased RSI at 40 weeks of PMA (odds ratio=1.23; P=0.01). RSI mediated 25% of the IsoP effect on DAYC motor scores (P=0.02) and had no significant impact on cognitive or communication scores. CONCLUSIONS: In the first month after birth, increases in plasma IsoPs identify preterm infants at risk for respiratory morbidity at term equivalent age and worse developmental outcomes at 12 months of CA. Poor neurodevelopment is largely independent of respiratory morbidity.