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Objective: This study aimed to assess the iron status prior to discharge in very low birth weight (VLBW) infants utilizing reticulocyte hemoglobin content (CHr) and evaluate the impact of delayed cord clamping (DCC) on iron status., Study Design: This is a retrospective analysis of VLBW infants from two tertiary level of care Neonatal Intensive Care Units. The primary outcome was the proportion of VLBW infants with low CHr (<29 pg) prior to discharge. Hematologic parameters were also compared between infants who received or did not receive DCC. Infants with a positive newborn screen for hemoglobin Bart's were excluded., Results: Among the 315 infants included, 99 infants (31.4%) had low CHr prior to discharge. The median (interquartile range) CHr prior to discharge was 30.8 pg (28.4-39 pg). DCC was performed in 46.7% of infants. Hemoglobin at birth, discharge, and CHr prior to discharge were higher and the need for blood transfusion and the number of infants with low CHr prior to discharge were lower in the DCC group., Conclusion: Approximately 31.4% of VLBW infants had low CHr near the time of discharge suggesting they were iron deficient. DCC improved hematological parameters prior to discharge in VLBW infants. CHr content can be used to guide iron supplementation in VLBW infants to potentially improve their iron status and long-term neurocognitive outcomes., Key Points: · DCC was associated with an improved hemoglobin and iron status at discharge in VLBW infants.. · CHr is an early and reliable marker for iron deficiency.. · Approximately one in three VLBW infants can be iron deficient at the time of discharge.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objectives: To investigate the association of growth patterns with overweight/obesity and markers of metabolic syndrome in ex-premature adolescents; to assess the relationship between the increase (1 SD) in Z-score weight at term and at 2 years with outcomes in adolescents with or without intrauterine growth restriction; and to evaluate the association between the Cook criteria and overweight/obesity according to body mass index., Methods: Cohort, retrospective, analytical study. Population: adolescents born weighting<1,500 g., Results: One hundred twenty-seven adolescents (11.3 years) were included. There is an association between the 1 SD increase in the percentile ( Pc ) of weight at 40 weeks and at 2 years in the population with adequate birth weight (PCA) with insulin levels, resistance, and sensitivity at 11 years. Catch-up at 2 years was associated with significantly higher proportion of HDL value<41 (18.75 vs. 5.36 %) OR 4.08 95% CI (1.04-16.05) p=0.031. Overweight/obesity was associated with waist circumference index>0.5, HDL<41, and with blood pressure greater than Pc 90 for sex and height., Conclusions: In preterm infants, a 1 SD increase in weight Z score at 40 weeks and 2 years was predictive of metabolic and cardiovascular disorders in adolescence., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: To determine the incidence of hyperferritinemia in VLBW infants, and its association with neonatal morbidity., Study Design: Prospective cohort study in a tertiary-level hospital in Bangkok, from March 2022 to January 2023. Serum ferritin (SF) was measured in VLBW infants at one month and repeated monthly for those with hyperferritinemia (SF > 300 ng/mL)., Results: Gestational age and birth weight were 29.7 ± 2.4 weeks (mean ± SD) and 1100 g (IQR, 830, 1340). Hyperferritinemia was identified in 30.1% (95% CI, 20.8-41.4). After adjustment, only packed red cell transfusion >15 mL/kg was associated with hyperferritinemia (RR 3.1; 95% CI, 1.5-6.4). All elevated SF levels returned to normal within four months. Hyperferritinemia was associated with severe bronchopulmonary dysplasia (RR 2.3, 95% CI, 1.0-5.4) and retinopathy of prematurity (RR 3.5, 95% CI, 1.4-8.6)., Conclusion: Hyperferritinemia is common among our VLBW infants, particularly after transfusion, and is associated with severe BPD and ROP., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To evaluate the efficacy of a strict glycaemic control protocol using a continuous glucose monitoring (CGM) in infants at high risk of dysglycaemia with the aim of reducing the number of dysglycaemic episodes., Design: Randomised controlled trial., Setting: Neonatal intensive care unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome., Patients: All infants <1500 g fed on parental nutrition (PN) since birth were eligible. A total of 63 infants were eligible and 48 were randomised., Intervention: All participants wore a CGM sensor and were randomised in two arms with alarms set at different cut-off values (2.61-10 mmol/L (47-180 mg/dL) vs 3.44-7.78 mmol/L (62-140 mg/dL)), representing the operative threshold requiring modulation of glucose infusion rate according to an innovative protocol., Main Outcome Measures: The primary outcome was the number of severe dysglycaemic episodes (<2.61 mmol/L (47 mg/dL) or >10 mmol/L (180 mg/dL)) in the intervention group versus the control group, during the monitoring time., Results: We enrolled 47 infants, with similar characteristics between the two arms. The number of dysglycaemic episodes and of infants with at least one episode of dysglycaemia was significantly lower in the intervention group (strict group): respectively, 1 (IQR 0-2) vs 3 (IQR 1-7); (p=0.005) and 12 (52%) vs 20 (83%); p=0.047. Infants managed using the strict protocol had a higher probability of having normal glycaemic values: relative risk 2.87 (95% CI 1.1 to 7.3). They spent more time in euglycaemia: 100% (IQR 97-100) vs 98% (IQR 94-99), p=0.036. The number needed to treat to avoid dysglycaemia episodes is 3.2 (95% CI 1.8 to 16.6)., Conclusion: We provide evidence that CGM, combined with a protocol for adjusting glucose infusion, can effectively reduce the episodes of dysglycaemia and increase the percentage of time spent in euglycaemia in very low birthweight infants receiving PN in the first week of life., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To assess the efficacy and safety of restrictive versus liberal red blood cell transfusion thresholds in very low birth weight infants., Methods: We searched MEDLINE, EMBASE, and Cochrane database without any language restrictions. The last search was conducted in August 15, 2020. All randomized controlled trials comparing the use of restrictive versus liberal red blood cell transfusion thresholds in very low birth weight (VLBW) infants were selected. Pooled risk ratio (RR) for dichotomous variable with 95% confidence intervals were assessed by a random-effects model. The primary outcome was all-cause mortality., Results: Overall, this meta-analysis included 6 randomized controlled trials comprising 3,483 participants. Restrictive transfusion does not increase the risk of all-cause mortality (RR, 0.99; 95% CI, 0.84 to 1.17; I2 = 0%; high-quality evidence), and does not increase the composite outcome of death or neurodevelopmental impairment (RR, 1.01, 95% CI, 0.93-1.09; I2 = 7%; high-quality evidence) or other serious adverse events. Results were similar in subgroup analyses of all-cause mortality by weight of infants, gestational age, male infants, and transfusion volume., Conclusions: In very low birth weight infants, a restrictive threshold for red blood cell transfusion was not associated with increased risk of all-cause mortality, in either short term or long term., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

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.

Objective: We investigated the relationship of serum potassium (K + ) and ionized calcium (iCa 2+ ) levels with the persistence of ductus arteriosus., Study Design: This retrospective cohort study included infants with birth weight < 1,500 g and gestational age < 32 weeks. Serum K + and iCa 2+ levels at the 1st and 48th hour of life were measured from samples. The difference between the two levels was calculated for both serum K + (ΔK + ) and iCa 2+ (ΔCa 2+ ). These values were compared between hemodynamically significant patent ductus arteriosus (hsPDA) and non-hsPDA., Results: Of 1,322 hospitalized preterm nonates, 1,196 were included in the study. Mean serum K + levels at the 1st and 48th hour were higher and iCa 2+ levels at the 1st and 48th hour were lower in hsPDA and non-hsPDA, respectively ( p  < 0.001). Ionized ΔCa 2+ (-0.06 ± 0.13 vs. -0.02 ± 0.12 mmol/L) was higher in hsPDA ( p  < 0.001)., Conclusion: We demonstrated that serum K + and iCa 2+ level might play a role in ductal constriction., Competing Interests: None declared., (Thieme. All rights reserved.)

Objectives Hyperglycaemia is a common metabolic disorder in very-low-birth-weight (VLBW) infants and is associated with increased morbidity and mortality. The objective is to describe the incidence, duration, episodes and distribution of hyperglycaemia during the first 7 days of life of VLBW infants. Methods This is a prospective cohort study of 60 newborns weighing <1,500 g. Blood glucose levels were monitored with a continuous glucose monitoring system (CGMS) during the first 7 days of life. Hyperglycaemia was defined as glucose ≥180 mg/dL (≥10 mmol/L). Results Incidence of hyperglycaemia recorded with the CGMS was 36.6% (95%CI: 24.6-50.1). In almost 74.6±5.48% of these cases the duration of the episode exceeded 30 min and in 45.25% (95%CI: 2.26-57.82) it exceeded 2 h. The condition occurred most frequently during the first 72 h of life. One-fifth of cases were not detected with scheduled capillary tests and 84.6% of these had hyperglycaemic episode durations of 30 min or more. Agreement between the two techniques was very good (r=0.90, p<0.001) and the CGMS proved to be reliable, accurate and safe. Hyperglycaemia detected by a CGMS is associated with lower gestational age (OR: 0.66, p=0.002), lower birth weight (OR: 0.99, p=0.003), the use of ionotropic drugs (OR: 11.07, p=0.005) and death (OR: 10.59, p=0.03), and is more frequent in preterm infants with sepsis (OR: 2.73, p=0.1). No other association was observed. Conclusions A CGMS could be useful during the first week of life in VLBW infants due to the high incidence and significant duration of hyperglycaemia and the high proportion of cases that remain undetected. The advantage of the CGMS is that it is able to detect hyperglycaemic episodes that the capillary test does not.

Background: Unbound free fatty acids (FFAu) are the bioactive fraction of plasma free fatty acids (FFA). Most plasma FFA are bound to albumin. Only when FFA dissociate from albumin, do they become biologically active. Objective: To measure the first FFAu profiles in human infants and to measure these profiles before and during intravenous administration of the soybean lipid, intralipid (IL). Study design: The study population was 16 premature infants, from a parent study of 130 infants with birth weights 500-2000 g and gestational age 23-34 weeks. The infants chosen had plasma samples of ≥120 µL (volume needed for each FFAu profile measurement) in the first day of life. Infants received IL infusions starting in the second day of life at 1 g/kg/day, increasing by 1-g/kg/day daily up to 3 g/kg/day. FFAu profiles were determined during IL infusion when plasma was available. Profiles are the concentrations of the nine most abundant long-chain FFAu and were determined using novel fluorescent probes. Results: Before intralipid infusion unbound myristic acid was the dominant FFAu, as high as 78% of the total FFAu (sum of the 9 FFAu). In contrast, unbound linoleic acid was 0% in all infants. With increasing infusion of IL to 3 g/kg/day, unbound linoleic increased to 26% of the total FFAu, with unbound oleic, myristic, and linolenic acid the second, third and fourth most abundant. The average total FFAu concentration also increased from 4 nM before intralipid to 53 nM at 3 g/kg/day. During IL infusion the FFAu profiles approached the fatty acid composition of intralipid at 3 g/kg/day. Conclusions: This first study of FFAu profiles in neonates revealed that before IL infusion unbound linoleic acid was zero in all 16 infants and levels of myristic acid were exceptionally large, as much as 78% of the total FFAu profile. These results suggest important and previously unrecognized roles of lipid metabolism in early development. Zero unbound linoleic acid before IL infusion may help promote closure of the ductus arteriosus but after IL infusion, synthesis of arachidonic from linoleic acid may tend to promote patency. The high levels of unbound myristate may be needed for immediate neonatal energy needs.

Background: Thrombocytopenia is a risk factor for patent ductus arteriosus. Immature and mature platelets exhibit distinct haemostatic properties; however, whether platelet maturity plays a role in postnatal, ductus arteriosus closure is unknown., Methods: In this observational study, counts of immature and mature platelets (=total platelet count - immature platelet count) were assessed on days 1, 3, and 7 of life in very low birth weight infants (<1500 g birth weight). We performed echocardiographic screening for haemodynamically significant patent ductus arteriosus on day 7., Results: Counts of mature platelets did not differ on day 1 in infants with (n = 24) and without (n = 45) haemodynamically significant patent ductus arteriosus, while infants with significant patent ductus arteriosus exhibited lower counts of mature platelet on postnatal days 3 and 7. Relative counts of immature platelets (fraction, in %) were higher in infants with patent ductus arteriosus on day 7 but not on days 1 and 3. Receiver operating characteristic curve analysis unraveled associations between both lower mature platelet counts and higher immature platelet fraction (percentage) values on days 3 and 7, with haemodynamically significant ductus arteriosus. Logistic regression analysis revealed that mature platelet counts, but not immature platelet fraction values, were independent predictors of haemodynamically significant patent ductus arteriosus., Conclusion: During the first week of postnatal life, lower counts of mature platelets and higher immature platelet fraction values are associated with haemodynamically significant patent ductus arteriosus. Lower counts of mature platelet were found to be independent predictors of haemodynamically significant patent ductus arteriosus.

Introduction: Deficiencies in innate immune responses may contribute to the increased susceptibility to infection in preterm infants. In vivo cytokine profiles in response to sepsis in very preterm infants are not fully understood., Aims: To characterise plasma pro- and anti-inflammatory cytokine concentrations and pre-defined ratios in very preterm infants with late-onset sepsis (LOS)., Methods: In this observational study, peripheral blood samples were collected at the time of evaluation for suspected LOS from 31 preterm infants (<30 weeks gestational age). Plasma cytokine concentrations were determined by 12-plex immunoassay., Results: IL-10, IFN-γ, IL-12p70, IP-10, IL-6 and CCL2 were elevated in the majority infants with LOS (n = 12) compared to those without LOS (n = 19). There was no difference in TNF-α, IL-1β, IL-17AF, IL-8 and IL-15 concentrations between groups. IL-10/TNF-α ratios were increased, while CCL2/IL-10 and IL-12p70/IL-10 ratios were decreased in infants with LOS compared to those without., Conclusion: Very preterm infants have a marked innate inflammatory response at the time of LOS. The increase in IL-10/TNF-α ratio may indicate early immune hypo-responsiveness. Longitudinal studies with a larger number of participants are required to understand immune responses and clinical outcomes following LOS in preterm infants., Competing Interests: The authors have declared that no competing interests exist.

Background: To assess the postnatal rate of rise (ROR) of total serum bilirubin (TSB) in very low birth weight (VLBW) preterm infants, to determine risk factors associated with a rapid rise (>90th percentile), and to compare ROR and hour-specific TSB at postnatal 12-48 h with data of term infants retrieved from the literature., Methods: Retrospective analysis of 2430 routine TSB concentrations obtained between birth and initiation of phototherapy in 483 VLBW infants., Results: TSB increased by a median (interquartile range) ROR of 0.15 (0.11-0.19) mg/dL/h. The 50th percentile of TSB was below the 40th percentile of (near-)term counterparts at 12-48 h. TSB ROR correlated with the age at initiation (R S  = -0.687; p < 0.001) and the duration (R S  = 0.444; p < 0.001) of phototherapy. ROR >90th percentile (>0.25 mg/dL/h) was associated with lower gestational ages [27.2 (25.4-29.3) vs. 28.4 (26.4-30.4) weeks], lower birth weights [978 (665-1120) vs. 1045 (814-1300) g], and lower 5-min Apgar scores [7 (7-8) vs. 8 (7-9)]., Conclusion: ROR of TSB is an indicator for early and prolonged phototherapy. While hour-specific TSB and ROR at 12-48 h are lower than those reported for (near-)term infants, TSB appears to rise more rapidly in infants with low gestational age, low birth weight, and low 5-min Apgar score.

Very preterm infants (VPI, born at or before 32 weeks of gestation) are at risk of adverse health outcomes, from which they might be partially protected with appropriate postnatal nutrition and growth. Metabolic processes or biochemical markers associated to extrauterine growth restriction (EUGR) have not been identified. We applied untargeted metabolomics to plasma samples of VPI with adequate weight for gestational age at birth and with different growth trajectories (29 well-grown, 22 EUGR) at the time of hospital discharge. A multivariate analysis showed significantly higher levels of amino-acids in well-grown patients. Other metabolites were also identified as statistically significant in the comparison between groups. Relevant differences (with corrections for multiple comparison) were found in levels of glycerophospholipids, sphingolipids and other lipids. Levels of many of the biochemical species decreased progressively as the level of growth restriction increased in severity. In conclusion, an untargeted metabolomic approach uncovered previously unknown differences in the levels of a range of plasma metabolites between well grown and EUGR infants at the time of discharge. Our findings open speculation about pathways involved in growth failure in preterm infants and the long-term relevance of this metabolic differences, as well as helping in the definition of potential biomarkers.

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.

Objective: This study aimed to determine if delayed cord clamping (DCC) is associated with a reduction in neonatal acute kidney injury (AKI)., Study Design: A retrospective single-center cohort study of 278 very low birth weight (VLBW) neonates was performed to compare the incidence of AKI in the following groups: immediate cord clamping (ICC), DCC, and umbilical cord milking. AKI was diagnosed by the modified neonatal Kidney Diseases and Improving Global Outcomes (KDIGO) definition., Results: The incidence of AKI in the first week was 20.1% with no difference between groups ( p  = 0.78). After adjustment for potential confounders, the odds of developing AKI, following DCC, compared with ICC was 0.93 (confidence interval [CI]: 0.46-1.86) with no reduction in the stage of AKI between groups., Conclusion: In this study, DCC was not associated with a reduced rate of AKI in VLBW neonates. However, the data suggest that DCC is also not harmful to the kidneys, further supporting the safety of DCC in VLBW neonates., Competing Interests: J.R.C. is co-owner of Sindri Technologies, LLC., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: N-terminal pro-B-type natriuretic peptide (NTproBNP) appears to be a useful tool for diagnosing hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. However, a consensus for its application has not been reached., Objective: The present study aims to evaluate the role of NTproBNP in predicting hsPDA in preterm infants, and explore the optimal cutoff value and testing-time., Methods: A prospective blind study of 120 preterm infants with birth weights of < 1,500 g was conducted at the NICU of Peking University Shenzhen Hospital. Blood samples were successively collected on the first three days after birth for NTproBNP analysis. Echocardiographies were performed on day three of life to confirm the status of the ductus arteriosus. A receiver operating characteristic curve (ROC) analysis was performed to determine the ability of NTproBNP to recognize hsPDA., Results: NTproBNP was significantly higher in infants with hsPDA, than in infants in the control group, on both day two (P < 0.001) and day three (P < 0.001). On day two, a NTproBNP cutoff value of 3,689.0 pmol/L offered an optimal predictive value for hsPDA, while on day three, the optimal cut-off value for hsPDA was 2,331.5 pmol/L. The investigators proposes day three of life (48-72 hours) as the optimal testing time., Conclusion: The NTproBNP biomarker during the early neonatal period can be a useful tool for screening and assessing hsPDA in premature infants, especially on day three of life.

Introduction: Besides programming of the hypothalamic-pituitary-adrenal (HPA) axis, changes in the activity of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) could contribute to the later metabolic and cardiovascular consequences of preterm birth., Objective: We compared serum cortisol, cortisone, and cortisol/cortisone ratio in early childhood in very-low-birthweight (VLBW) infants and term appropriate for gestational age (AGA) born infants., Methods: We included 41 VLBW infants, participating in the randomized controlled Neonatal Insulin Replacement Therapy in Europe trial, and 64 term AGA-born infants. Cortisol and cortisone were measured in blood samples taken at 6 months and 2 years corrected age (VLBW children) and at 3 months and 1 and 2 years (term children). At 2 years of (corrected) age (HDL) cholesterol, triglycerides, glucose, and insulin were also measured., Results: During the first 2 years of life, cortisol/cortisone ratio is higher in VLBW children compared to term children. In the total group of children, cortisol/cortisone ratio is positively related to triglycerides at 2 years of (corrected) age. In VLBW children, over the first 2 years of life both cortisol and cortisone are higher in the early-insulin group compared to the standard care group., Conclusions: In VLBW infants, lower 11β-HSD2 activity probably contributes to the long-term metabolic and cardiovascular risks. In VLBW infants, early insulin treatment could affect programming of the HPA axis, resulting in higher cortisol and cortisone levels during early childhood., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Objective: The aim of this study was to assess the utility of early postnatal platelet indices in the prediction of hemodynamically significant patent ductus arteriosus (hsPDA) and its response to pharmacological treatment in preterm infants., Study Design: The medical records of 971 infants with gestational age < 30 weeks and birth weight < 1,500 g were analyzed retrospectively. Infants with hsPDA comprised the study group and those without hsPDA comprised the control group. Complete blood count results were recorded, and red cell distribution width-to-platelet ratio (RPR) and platelet mass were calculated., Results: A total of 481 infants, 169 in the hsPDA group and 312 in the control group, were included. In terms of platelet indices, the hsPDA group showed significantly lower mean platelet volume (MPV) and platelet mass, whereas RPR was significantly higher ( p  < 0.05, respectively). Multiple logistic regression analysis showed that RDS (relative ratio [RR]: 2.39; 95% confidence interval [CI]: 1.45-3.93; p  < 0.001), MPV < 7.85 (RR: 3.71; 95% CI: 2.29-6.01; p  < 0.001), and RPR > 0.070 (RR: 5.33; 95% CI: 3.28-8.65; p  < 0.001) were independent risk factors for hsPDA., Conclusion: Low MPV and platelet mass and high RPR in the first hours of life are risk factors for hsPDA and hsPDA refractive to pharmacological treatment with ibuprofen in preterm infants., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: The aim of our study was to measure the basal serum cortisol concentration immediately after birth and to determine its association with perinatal factors and clinical outcomes in very low birth weight (VLBW) infants., Methods: Basal serum cortisol level was obtained within one hour after birth in inborn VLBW infants. The association between the basal serum cortisol level and perinatal and clinical outcomes was analyzed by comparing the groups with high versus low cortisol levels., Results: In total, 80 infants were included. The median concentration of basal serum cortisol was 167 nmol/L with an interquartile range of 98-298 nmol/L. The basal serum cortisol concentration positively correlated with elapsed time from the last betamethasone dose. Low serum cortisol concentration was associated with antenatal corticosteroid therapy, low lactic acid level, and low leukocyte count at birth. Basal serum cortisol level was not associated with mortality and neonatal morbidities including hypotension and severe grade intraventricular hemorrhage., Conclusion: Both maternal corticosteroid therapy and perinatal distress may affect the basal serum cortisol concentration in VLBW infants early after birth., (Copyright © 2019. Published by Elsevier B.V.)

Background: The aim of this study was to follow the growth and hematological indicators of preterm infants during their first year., Methods: Neonates below 37 gestational weeks had routine follow-ups up through 1 year from January 2012 to December 2015 at West China 2nd University Hospital, Sichuan University. Weight, length and head circumference (HC) were measured monthly during the first 6 months, followed by monitoring every second month until 12 months. The catch-up growth defined as a gain of Z-score > 0.67 according to previous study. All preterm infants were prescribed iron prophylaxis based on national guideline. The hemoglobin concentration was examined at 6 and 12 months., Results: Altogether, 132 very-low-birth-weight (VLBW), 504 low-birth-weight (LBW) and 198 normal-birth-weight (NBW) infants were followed. The rates of catch-up growth for weight, length and HC 12 months of corrected age (CA) were 22.6, 29.1 and 14.6%, respectively. SGA and VLBW infants showed higher catch-up growth rates. The overall prevalence of anemia was 6.8% at 6 months and 7.8% at 12 months. The Z-scores for weight-for-length, length and HC were lower in the VLBW and SGA preterm infant groups than in the other preterm groups throughout the first year of life. The incidences of stunting, microcephaly and wasting changed from 5, 1.3 and 3.7% to 2, 1.1, 0.9 and 2.4%, respectively, during the first year. However, the incidences of wasting and stunting were higher for the VLBW infants than for the LBW and NBW infants at 12 months (9.3% vs. 1.4%, p < 0.01; 9.3% vs. 1%, p < 0.01,respectively; 4.7% vs. 0.8%, p < 0.01, 4.7% vs. 0%, p < 0.01,respectively). Similar results were observed between SGA and AGA infants (8.7% vs. 1.5%, p < 0.01; 5.8% vs. 0.4%, p < 0.01). Logistic regression revealed SGA and VLBW as risk factors for poor growth (WLZ < -2SD) at 12 months (OR = 5.5, 95% CI: 2.1-14.8, p < 0.01: OR = 4.8, 95% CI: 1.8-12.8, p < 0.01, respectively)., Conclusion: The VLBW and SGA preterm infants showed significant catch-up growth during their first year of life. However, SGA and VLBW were risk factors for poor growth during the preterm infants' first year of life. Prophylactic iron supplementation in preterm infants appears to reduce the prevalence of anemia.

Objective: This article identifies the prevalence and associated factors of hypophosphatemia (HP) in very low birth weight (VLBW) infants in the first week of life., Study Design: Prospective exploratory cohort study of 106 consecutive VLBW infants admitted to neonatal intensive care at Foothills Hospital, Calgary, Canada. HP was defined as at least one measurement of serum phosphate < 1.5 mmol/L (4.5 mg/dL)., Results: Seventy-seven percent (82/106) of the VLBW infants had HP, with significantly higher prevalence in infants < 1,000 g (94%) compared to infants ≥ 1,000 g (61%) ( p  < 0.001). Hypophosphatemic infants had lower birth weight ( p  < 0.001), gestational age ( p  < 0.001), and their increase in phosphate intake was slower ( p  = 0.003). Respiratory distress syndrome (RDS) ( p  = 0.002), intraventricular hemorrhage (IVH) ≥ grade III ( p  = 0.020), and hyperglycemia ( p  = 0.013) were more frequent among hypophosphatemic infants, especially among those < 1,000 g. Mortality, seizures, arrhythmias, and need for transfusion were not different between groups. Birth weight modified the association between RDS, IVH, hyperglycemia, and HP., Conclusion: HP was ubiquitous among infants < 1,000 g and highly prevalent among those weighing 1,000 to 1,500 g. While the direction of effect was not clear, RDS, IVH, and hyperglycemia were associated with HP. Prevention of HP in these physiologically immature neonates might improve neonatal outcomes., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Fetal atrioventricular block is a rare pathology, mostly due to placental transmission of maternal SSA/Ro and SSB/La antibodies, and can lead to severe fetal or neonatal outcomes. We report a case of dichorionic, diamniotic twin pregnancy, with maternal SSA/Ro antibodies. Isolated complete atrioventricular block was diagnosed at 23 weeks in one fetus (Twin A), while the second fetus (Twin B) remained in normal sinus rhythm. Severe asymmetric intrauterine growth restriction occurred in Twin A. Delivery was by caesarean section at 32 + 2 weeks. Neonatal permanent pacemaker was inserted on the first day after birth in 1140 g neonate. Discordant heart block in twin pregnancy has already been reported in a few dichorionic pregnancies, but the pathway of discordant disease expression remains unclear. Extraction decision is a dilemma between cardiac failure prevention and prematurity associated twin morbidity. This case shows a successful pacing in a very low birth weight neonate., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

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.

Objective: The aim of this study is to establish the serum level distribution of cortisol and ACTH in VLBW preterm newborns and determine which neonates are ideal candidates for the stimulation test for adrenal insufficiency., Methods: Plasma cortisol and ACTH levels were evaluated in 416 VLBW newborns on days 1, 7, and 30 of life. Gender, gestational age, weight, type of delivery, RDS prophylaxis, and perinatal morbidities were considered as potential variability factors., Results: Cortisol and ACTH levels significantly decreased between 1, 7, and 30 days. Significantly higher cortisol levels were found at lower gestational ages and in infants born by vaginal delivery, whereas lower levels were observed in those born after maternal corticosteroid treatment. The distribution of cortisol and ACTH levels in healthy infants born by cesarian section is presented., Conclusion: Even if high or low levels were not frequently linked to illness, the presented distribution data may indicate that the newborns are ideal candidates for the stimulation test.

Objective: Patent ductus arteriosus (PDA) is an important clinical problem associated with mortality and serious morbidities. It is thought that serum osmolality may affect ductal patency. We aimed to investigate the importance of serum osmolality related to ductal patency in preterm infants., Study Design: Our study was conducted between January 2013 and December 2017. Premature infants with birth weight <1,500 g and gestational age <32 weeks were included in the study. Serum osmolality was compared between infants with hemodynamically significant PDA (hsPDA) and non-hsPDA., Results: During the study period, 799 patients were evaluated. Mean serum osmolality levels were higher in the "hsPDA" group (297 ± 10.9 vs. 292 ± 8.3 mOsm/L) ( p  = 0.001). The area under the curve for osmolality was 0.582 ( p  = 0.0006, 95% confidence interval: 0.541-0.622) at the time of diagnosis for predicting hsPDA, with a cutoff value for osmolality of 300 mOsm/L., Conclusion: Serum osmolality may be recognized as an important contributing factor for ductal patency especially among extremely preterm infants who are most likely to have hsPDA in the early days of life., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Introduction: Low birth weight (LBW, <2500 g) may predict an increased risk of an adverse cardiometabolic profile later in life, but long-term effects in different populations and birth weight strata are still unclear. We explored laboratory markers of cardiometabolic risk in children born with marginally LBW (2000-2500 g)., Methods: This was a prospective longitudinal cohort study including 285 Swedish marginally LBW children and 95 normal birth weight (NBW, 2501-4500 g) controls. At 3.5 and 7 years of age, blood samples for glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), cholesterol, triglycerides, high- and low density lipoprotein (HDL and LDL), apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) were assessed and compared between the groups., Results: No significant differences in levels of insulin, HOMA-IR, hs-CRP or blood lipids were observed between marginally LBW and NBW children. At 7 years there was a higher proportion of marginally LBW children with elevated levels of insulin, defined as above the 90th percentile of the control group (21% vs 8.6%, p = 0.038). This association was, however, confounded by maternal ethnicity. In marginally LBW children born small for gestational age (SGA), mean fasting glucose was significantly higher compared to controls (4.7 vs 4.5 mmol/L, p = 0.020)., Conclusions: There were no significant differences in insulin, insulin resistance, hs-CRP or blood lipids between the marginally LBW children and controls. The subgroup of marginally LBW children born SGA may present early signs of glucose imbalance already at school age., Competing Interests: The authors have declared that no competing interests exist.

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.

The human major histocompatibility complex class I chain-related gene A and B (MICA and MICB) is one of the genes in chromosome 6. As MIC expression is inducible by heat, viral infection, inflammation and DNA damage, the molecules have been thought to be stress markers for the cells. We aimed to find the level of mRNA concentrations of MICA and MICB in neonates without any evidence of early onset infection.

Aims: Infection-induced inflammation is associated with adverse long-term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants., Method: An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12 h for two days (60 mg kg -1 per 12 h), and in infants with confirmed diagnosis of LOS or NEC, for 6 h for another 4 days (30 mg kg -1 per 6 h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling., Results: The preterm infants (n = 26) had a median (range) gestation of 24.8 weeks (23.3-30.4) and birthweight of 689 g (370-1285). PTX was well tolerated and without treatment-limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six-fold difference in exposure between 24 and 35 weeks postmenstrual age., Conclusions: The developed model can be used to explore dosing strategies based on size and maturation for preterm infants., (© 2018 The British Pharmacological Society.)

Background: This study aimed to compare the effects of adjustable fortification (AF), targeted fortification (TF), and standard fortification (SF) methods on the early growth of very low birth weight infants., Materials and Methods: Sixty infants <32 weeks of gestational age and weighing <1,500 g were selected. These infants were exclusively fed with breast milk and were randomized into three fortification groups: SF, AF, and TF. SF consists of adding a fixed amount of fortifier to maternal milk. Blood urea nitrogen levels are used to adjust fortifier in AF. In TF, breast milk is analyzed and fortified accordingly based on the macronutrient content to achieve the targeted intake., Results: A total of 76 preterm infants were eligible for the study. Sixty infants were randomized into three groups. At the end of the fourth week of fortification period, median daily weight gain of the infants was similar in the AF [23.5 g/(kg·d)] and TF groups [25.5 g/(kg·d)], and significantly higher in both groups than in SF group [12 g/(kg·d)] (AF versus SF group, p < 0.001 and TF versus SF group, p < 0.001). Weight, head circumference, and length were compared across the three groups regarding percentile. Significant improvement in the percentile groups of weight and head circumference was observed in the AF and TF groups. In the SF group, a significant decline in the percentile groups of weight, head circumference, and length was detected. Daily protein and energy intakes in AF and TF groups were significantly higher than those in SF group (SF versus AF, p < 0.001 and SF versus TF, p < 0.001)., Conclusions: Fortifying breast milk with AF and TF methods was found to improve body weight, length, and head circumference percentiles of preterm infants, whereas SF method was found unsatisfactory. To provide optimum growth for preterm babies, breast milk that has been fortified by using AF and TF strategies should be recommended in neonatal intensive care units.

Purpose: Ischemia-modified albumin (IMA) is used to determine tissue hypoxia. We aimed to evaluate the serum IMA levels in preterm infants requiring transfusion due to anemia of prematurity, a clinical condition to cause tissue hypoxia., Materials and Methods: This prospective study was performed in Etlik Zubeyde Hanim Hospital, Turkey. Preterm infants with birth weight less than 1500 g and born between 25 and 32 weeks were included during assessment for anemia of prematurity. The transfused infants with anemia of prematurity formed the "transfusion group", the control group consisted of gender, gestational and postnatal age-matched infants without transfusion requirement. Serum samples of control group and pre-transfusion and post-transfusion samples of transfusion group were analyzed for IMA (ABS unit). Serum IMA levels were compared between control group and pre-transfusion samples of transfusion group and were also evaluated for the significance of change after transfusion., Results: Sixty-two infants were included (transfusion group: 31, control group: 31). The pretransfusion serum IMA levels were higher than that of infants in the control group [ABS unit; transfusion group; pre-transfusion: 1.00 (0.76-1.09) and control group: 0.81 (0.52?1.04); p = .03]. Serum IMA levels decreased significantly to 0.79 (0.59-0.95) after transfusion; p = .007. Infants with hematocrit higher than 30% had lower IMA levels [0.69 (0.54-0.96)] than infants with lower hematocrit [0.96 (0.75-1.05)]; p = .002., Conclusions: Clinicians may bear in mind that serum IMA levels could be utilized as a marker in deciding on erythrocyte transfusion in premature anemia.

Background: Glucose variability (GV) is a matter of interest for researches in recent years. It is connected with oxidative stress, which is crucial in the development of multiple complication of prematurity. However, glycemic variability in preterm infants was poorly investigated. This study aims to investigate glycemic variability obtained from a continuous glucose monitoring (CGM) system in a cohort of very low-birthweight (VLBW) infants., Methods: A prospective, single-center, open cohort study enrolled 74 VLBW infants with a mean birthweight of 1066 g and median gestational age of 28 weeks. A CGM system (Guardian Real-Time CGM ® , Medtronic, Northridge, CA) was used to measure interstitial glucose concentration. The glycemic variability was calculated using EasyGV., Results: Most glycemic variability indices in VLBW infants showed log-normal distribution and for these, geometric mean ÷/ × geometric standard deviation (GSD) was calculated: M-value 2.28 (÷/ × 1.82), mean amplitude of glycemic excursions (MAGE) 1.89 (÷/ × 1.34), average daily risk ratio (ADRR) 2.22 (÷/ × 2.56), lability index 0.46 (÷/ × 1.71), J-index 0.46 (÷/ × 1.71), low blood glucose index 2.05 (÷/ × 1.66), high blood glucose index 1.11 (÷/ × 2.44), continuous overlapping net glycemic action (CONGA) 5.54 (÷/ × 1.16), mean of daily differences (MODD) 1.23 (÷/ × 1.38), and coefficient of variation 1.15 (÷/ × 1.31). Only SD of glucose concentration showed a normal distribution: arithmetic mean 1.24 (+/-0.37). ADRR, J-index, MODD, CONGA, and MAGE are moderately to strongly correlated with SD., Conclusions: In our cohort of VLBW infants, almost all glycemic variability indices showed skewed positive distribution. The natural central tendency measure for the log-normally distributed data is the geometric mean and for statistical variation is the GSD.

Premature infants represent one of the groups with increased risk for metabolic syndrome. Our study is the first one to evaluate irisin and visfatin levels, associated with the metabolic syndrome, both in blood of preterm and full-term infants, as well as in the breastmilk of their mothers. A total of 72 newborns was enrolled in the study, including 53 very low birth weight preterm infants and a control group of 19 term infants. The levels of irisin and visfatin were determined by a commercial enzyme-linked immunoabsorbent assay both in the baby serum and maternal milk twice, first during the 1st week of life and then 4 weeks later. Preterm infants had significantly lower serum irisin levels compared to the term infants. Overall, serum irisin level during the 1st week of life was positively correlated with several anthropometric measurements at birth, as well as during 5th weeks of age. In contrast, serum visfatin levels during 5th week of life were negatively correlated with z-scores of birth weight, weight and head circumference during 5th week of age. We found a strong negative correlation between serum irisin and serum visfatin levels at both analyzed time points. The level of milk visfatin was significantly higher in the mothers of the preterm group during 5th week of life. In conclusion, our results provide further evidence that irisin and visfatin may play physiologic roles in development of both preterm and full-term newborns during their first month after birth. Observed differences in irisin and visfatin serum and breastmilk concentrations during the earliest stages of life may contribute to development of catch up growth, but also, they might eventually lead to a higher risk for metabolic syndrome in prematurely born children in later years., Competing Interests: The authors have declared that no competing interests exist.

Background: Amino acid (AA) and acylcarnitine (AC) are important biomarkers of protein and fatty acid metabolism. Examining their levels in newborns may reveal multiple inherited metabolic diseases. However, they have rarely been assessed in very low birth weight (VLBW) neonates, low birth weight (LBW) neonates and rarely been compared with normal weight (NW) neonates. The aim of the study was to identify the AA and AC profiles in dried blood spot (DBS) specimens of LBW and VLBW neonates, then compare with NW neonates, and make a contribution to the determination of cutoff values of VLBW and LBW neonates., Methods: Liquid Chromatography tandem mass spectrometry (LC/MS/MS) is an excellent tool for quantitatively detecting AA and AC profiles. This article verified the precision, accuracy, and linearity of the LC/MS/MS method in AA and AC detection, then analyzed AA and AC profiles in DBS of VLBW, LBW and NW neonates, and compared the difference of AA and AC in the three groups., Results: The results showed that the LC/MS/MS method had wide linear range, satisfied precision and reproducibility in detecting AA and AC in DBS specimens; most AA and AC concentrations significantly correlated with birth weight in DBS samples (p < 0.05)., Conclusions: The results suggested that VLBW and LBW neonates have different metabolic or nutritional status with NW neonates and different AA and AC cutoffs should be defined for them to reduce the risk of false-positive cases.

Objective: To assess whether early NT-ProBNP can identify the need for echocardiographic assessment of hemodynamically significant patent ductus arteriosus (HsPDA) in preterm infants., Study Design: Prospective observational study of infants with a gestational age ≤32 weeks. Echocardiographic assessment and NT-proBNP measurement were performed at 48-96 h. ROC curves were generated to assess optimal cutoffs to detect HsPDA and predict the need for treatment., Results: Eighty-five patients were included. HsPDA was present in 28 infants (37.6%), and 22 (25.8%) received treatment. The optimal NT-proBNP cutoff for the detection of HsPDA was 5099 pg/mL (sensitivity 94%, specificity 82%, area under the curve 0.941, P < 0.001). Only 1 child with NT-proBNP levels <5099 pg/mL was ultimately treated for PDA. NT-proBNP screening could have avoided 45 of 85 routine echocardiograms (53%)., Conclusion: NT-proBNP screening at 48-96 h of life may identify preterm infants at low risk for HsPDA, improving PDA management.

Parenteral nutrition-associated cholestasis (PNAC) has been linked to plasma accumulation of phytosterols in infants receiving vegetable-oil-based lipid emulsions (LE). To date, information on the ability of infants with PNAC to metabolize intravenous (IV) phytosterols has been very limited. We characterized plasma phytosterol half-life in very low birth weight (VLBW) preterm infants with PNAC. As part of a prospective cohort study, VLBW infants with PNAC underwent serial blood sample measurements of sitosterol (Sito), campesterol (Camp), and stigmasterol (Stigma). Infants without PNAC served as controls (CTRL, control infants). Thirty-seven PNAC infants and 14 CTRL were studied. On PN day 7 and PN day 14, PNAC infants had higher plasma phytosterol concentrations compared to those of CTRL (p < 0.05). A significant and positive correlation was found between plasma Camp, Stigma, Sito concentrations, and IV phytosterol intake from birth to PN day 7 (p = 0.001, p = 0.001, and p = 0.005, respectively). Stigma concentration was positively correlated with conjugated bilirubin on PN day 7 (p = 0.012). After stopping IV LE, half-lives of Camp, Stigma, and Sito became significantly longer in PNAC infants than in CTRL (Camp: 18.8 ±6.2 vs 11.8 ±3.0 days, p = 0.001; Stigma: 13.8 ±5.8 vs 9.4 ±3.4 days, p = 0.023; Sito: 15.3 ±5.0 vs 9.8 ±3.0 days, p = 0.002). In conclusion, phytosterols increased earlier during PN and were eliminated slowly after stopping IV LE in PNAC infants than in CTRL. The Stigma concentration on PN day 7 could represent an early marker of cholestasis. Our results provide additional evidence on the relationship between IV phytosterols and PNAC., (© 2018 AOCS.)

Background: Refeeding Syndrome (RFS) is a well-known group of symptoms which occur after the introduction of enteral or parenteral nutrition in undernourished patients. Intrauterine growth restriction (IUGR) is the equivalent of postnatal RFS following the beginning of feeding. The aggressive parenteral nutrition of neonates with very low birth weight (VLBW) resulting from the termination of intrauterine transplacental nutrition is a source of biochemical disorders., Objectives: The aim of this study was to analyze metabolic disorders in preterm infants during the 1st week of life and to determine the hypophosphatemia risk factors in low birth weight neonates receiving parenteral nutrition. The retrospective analysis covered 49 neonates, aged between 24 0/7 and 32 6/7 weeks of gestation., Material and Methods: The examined patients were divided into 2 groups according to the level of phosphates during the 1st week of life: HP (n = 18) with aggravated hypophosphatemia (≤3.1 mg/dL) and NP (n = 31) with normal phosphatemia (>3.1 mg/dL)., Results: Hypophosphatemia was observed in the first days of life in 61% of children, in 45% of whom a subsequent test revealed a further fall in the phosphate level. In the rest of the preterm neonates (39%), hypophosphatemia was revealed between the 4th and 7th day of life. The risk of early hypophosphatemia was higher in neonates with IUGR (p = 0.0001; RR 5.2, 95% CI 2.2–12.4) and extremely low birth weight (ELBW) preterm infants (p < 0.05)., Conclusions: Early hypophosphatemia should be closely monitored early in life, especially in newborns with ELBW and IUGR. Further research is needed to develop an optimal nutritional regimen from the first days of life.

Objectives: Early hyperglycemia is prevalent in preterm infants receiving parenteral nutrition (PN) therapy. Chromium improves glucose tolerance by potentiating the action of insulin. Therefore, we hypothesized that supplementing PN with chromium would improve glucose tolerance and PN calorie delivery in infants during the first week of life., Methods: We collected data on neonates receiving PN initiated at birth with chromium (0.2 mcg/kg/d) started either on days 5-7 (group A) vs day 1 (group B) on PN and compared glucose tolerance and PN calorie administration over the first week of life., Results: For similar mean serum glucose concentrations between group A (n = 348) and B (n = 358) (107 ± 48 vs 111 ± 52 mg/dL, P = .3), infants in group B tolerated higher glucose infusion rates and received more PN calories during the first week of life: 8.4 ± 2 vs 8 ± 2 mg/kg/min (P < .001) and 74.8 ± 23 vs 71.5 ± 12 kcal/kg/d (P = .017), respectively. The difference in calories delivered was more pronounced among very low birth weight (VLBW) infants compared with infants >1500 g: 76.5 ± 14 vs 72.4 ± 11 kcal/kg/d (P = .009) and 73.8 ± 27 vs 70.3 ± 12 kcal/kg/d (P = .079), respectively., Conclusions: PN chromium supplementation resulted in better glucose tolerance and calorie delivery during the first week of life, especially in VLBW infants. This supports chromium's essential role in enhancing glucose tolerance during PN therapy in VLBW infants at risk for early hyperglycemia., (© 2017 American Society for Parenteral and Enteral Nutrition.)

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.

Objective: To identify the vitamin D status to optimize calcium and bone health in preterm infants., Study Design: Very low birth weight infants had measurement of 25-hydroxyvitamin D status and markers of calcium and bone health from birth to term age. Piecewise linear regression modeling was performed to identify a 25-hydroxyvitamin D threshold associated with stable parathyroid hormone concentration and bone mineralization., Results: In a cohort of 89 infants at term age, femur BMC and density increased linearly with 25-hydroxyvitamin D status until reaching a threshold of 48 ng/mL and 46 ng/mL, respectively. Parathyroid hormone status decreased as vitamin D status increased until reaching a plateau at 25-hydroxyvitamin D of 42 ng/mL., Conclusion: Preterm infant vitamin D status was significantly associated with PTH status and femur mineralization with suggestion that achieving a specific 25-hydroxyvitamin concentration is associated with optimal calcium homeostasis and femur bone mineralization.

Background and Objective: Vitamin D supplementation in preterm infants has been recommended by American Academy of Pediatrics (AAP); however, its efficacy and safety has not been well studied. To study 25-hydroxy vitamin D (25OHD) levels as a marker of vitamin D status of very low birth weight infants while on vitamin D supplementation during neonatal intensive care unit hospitalization., Methods: Retrospective study of preterm infants with birth weight <1500 g admitted to our unit from January 2013 to December 2015 who were on oral vitamin D3 400 IU supplementation. Serum 25OHD level were checked at 4, 8, and 12 weeks of age or before discharge and the levels were stratified as deficient <20 ng/mL, insufficient 20 to 29 ng/mL, normal 30 to 60 ng/mL, high 61 to 100 ng/mL and very high >100 ng/mL., Results: A total of 301 infants were enrolled, 186 very low birth weight (VLBW; 1000-1499 g) infants and 115 extremely low birth weight (ELBW; <1000 g) infants. Approximately 80% of both VLBWs and ELBWs had deficient or insufficient 25OHD levels at 4 weeks of age. On oral vitamin D supplementation, VLBW infants increased their 25OHD levels significantly by 8 and 12 weeks of age, whereas ELBW infants lagged behind at 8 weeks and increased their 25OHD levels by 12 weeks of age., Conclusions: Eighty percent of ELBW and VLBW infants have either deficient or insufficient vitamin D status at 4 weeks of age. Vitamin D supplementation helps in improving the vitamin D levels, VLBW infants significantly more than ELBW infants. AAP recommendation appears to be safe; however, if using higher supplement dosing, 25OHD level should be monitored to avoid high and very high vitamin D levels.

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., (© 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

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)., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Careful control of glucose homeostasis is essential for infants with very low birth weight (VLBW). In clinical practice, blood and urine glucose levels are monitored; however, their correlation has not been fully investigated in VLBW infants., Objectives: To evaluate the correlation between interstitial fluid glucose concentration (ISFG), glycosuria, and urine output among VLBW infants through continuous glucose monitoring (CGM)., Methods: A prospective, single-center, open cohort study enrolled 74 VLBW infants with a mean birth weight of 1,066 g. CGM (Guardian Real-Time CGM®; Medtronic, Northridge, CA, USA) was used to measure glucose. The urine output was calculated using 4-hour intervals. Reagent strips were used for semiquantitative measurement of glycosuria., Results: The CGM delivered 102,334 glucose measurements. 2,684 urine samples were checked for glycosuria, of which 92.06% remained negative. Corresponding glycemia in samples without glycosuria remained normoglycemic (median 103 mg/dL; 10-90th percentile 80-144 mg/dL). The median glucose concentrations for samples in ascending glycosuria categories 1+, 2+, 3+, and 4+ were 152, 181, 214, and 222 mg/dL, respectively. A moderate correlation between ISFG and urine output was found for categories ≥1+ (rs = 0.56; 95% confidence interval 0.42-0.68; p < 0.001). The urine output was significantly lower when glycosuria was absent (p < 0.05). Polyuria was observed only in glycosuria 4+ (median urine output 9.9; interquartile range 7.4-12.2 mL/kg/h)., Conclusions: The renal glucose threshold in VLBW infants is between 150 and 180 mg/dL. A negative result for glycosuria is a reliable screening test to exclude hyperglycemia. Occurrence of glycosuria ≥1+ is an indication to test blood glucose., (© 2018 S. Karger AG, Basel.)

Background/aims: An increased preterm birth survival rate is associated with long-term neurological and metabolic risks; thus, our aim was to evaluate whether early patterns of infancy anthropometry and metabolic hormonal profile differ in preterm infants born small for gestational age (SGA) or appropriate for gestational age (AGA) from birth to 36 months of corrected age (CA)., Methods: We recruited 110 very-low-birth-weight (VLBW) preterm infants (AGA = 60 and SGA = 50) with a mean birth weight of -2.39 ± 0.77 versus 0.57 ± 0.54 standard deviation scores (SDS) (p < 0.01) and birth length of -2.1 ± 1.05 versus -0.44 ± 0.82 SDS (p < 0.01), respectively. Anthropometry and blood sampling for insulin, insulin-like growth factor (IGF)-II, IGF-I, and leptin were performed for up to 3 years., Results: All neonates increased their weight, length, and head circumference SDS during the early inpatient period. Up to 90% reached a normal length within this period. The IGF-II, insulin, and glycemia concentrations changed in parallel with weight. In the first year of CA, only SGA infants gained weight and height SDS. The homoeostatic model assessment had a trend toward higher values in SGA infants at 24 and 36 months (p = 0.06 and p = 0.07)., Conclusion: Being SGA is the strongest predictor of early recovery of height in VLBW preterm infants. Follow-up will allow us to determine whether the differences in the growth patterns of VLBW preterm infants by birth weight SDS persist., (© 2018 S. Karger AG, Basel.)