Biomarkers of Kidney Injury in Very-low-birth-weight Preterm Infants: Influence of Maternal and Neonatal Factors.

BACKGROUND/AIM: Acute kidney injury is an important cause of mortality in very-low-birth-weight (VLBW) preterm infants. As in the general population, the detection of renal damage cannot rely on the measurement of serum creatinine, since it has been demonstrated to be a weak predictor and a delayed indicator of kidney function deterioration. However, several candidate biomarkers have failed to prove sufficient specificity and sensitivity for a routine clinical use because of the poor awareness of their biological role. This study was aimed to investigate the impact of different maternal and neonatal conditions on several renal biomarkers in VLBW preterm infants during the first week of life. PATIENTS AND METHODS: Preterm infants<32 weeks' gestation and <1500g were enrolled. We measured urinary biomarkers kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, epidermal growth factor (EGF) and osteopontin (OPN) on the 1st, 3rd, and 7th day after birth. RESULTS: Thirty-tree infants were included. The multivariate analysis showed a significant association between gestational age, the presence of patent ductus arteriosus, antenatal maternal hypertension and the levels of urinary biomarkers. CONCLUSION: There is a possible relation between early biomarkers of renal injury and antenatal, perinatal and post-natal characteristics in VLBW preterm infants during the first week of life.

Free radicals and neonatal encephalopathy: mechanisms of injury, biomarkers, and antioxidant treatment perspectives.

Neonatal encephalopathy (NE), most commonly a result of the disruption of cerebral oxygen delivery, is the leading cause of neurologic disability in term neonates. Given the key role of free radicals in brain injury development following hypoxia-ischemia-reperfusion, several oxidative biomarkers have been explored in preclinical and clinical models of NE. Among these, antioxidant enzyme activity, uric acid excretion, nitric oxide, malondialdehyde, and non-protein-bound iron have shown promising results as possible predictors of NE severity and outcome. Owing to high costs and technical complexity, however, their routine use in clinical practice is still limited. Several strategies aimed at reducing free radical production or upregulating physiological scavengers have been proposed for NE. Room-air resuscitation has proved to reduce oxidative stress following perinatal asphyxia and is now universally adopted. A number of medications endowed with antioxidant properties, such as melatonin, erythropoietin, allopurinol, or N-acetylcysteine, have also shown potential neuroprotective effects in perinatal asphyxia; nevertheless, further evidence is needed before these antioxidant approaches could be implemented as standard care.

Effect of Different Tube Feeding Methods on the Delivery of Docosahexaenoic and Arachidonic Acid: An In Vitro Pilot Study.

BACKGROUND: Arachidonic acid (AA) and docosahexaenoic acid (DHA) are crucial for neural and visual development after premature birth. Preterm infants usually require tube feeding (TF) until the achievement of adequate oral feeding skills; the impact of TF on DHA and AA delivery has not been investigated yet. This study aimed to evaluate the effect of different TF techniques on the delivery of AA and DHA contained in human milk (HM). METHODS: HM samples (65 mL each) were collected and divided into three 20-mL aliquots. The remaining 5 mL served as baseline. Three TF techniques were simulated (1 for each aliquot): gravity bolus feeding (BF), 3-hour continuous feeding using a horizontal feeding pump, and 3-hour continuous feeding with the feeding pump angled at 45°. For horizontal continuous feeding (HCF) and 45° angled continuous feeding (ACF), aliquots delivered between 0 and 90 minutes (T1) and 91 and 180 minutes (T2) were collected separately. AA and DHA concentration was analyzed by gas chromatography/mass spectrometry and compared among the TF methods. DHA and AA delivery at T1 and T2 was also evaluated. RESULTS: Fifty-one simulated feeds were performed. DHA and AA amounts after BF and ACF did not differ significantly compared with baseline, whereas HCF resulted in significantly lower DHA and AA concentration. During T2, ACF delivered almost twice the DHA and AA amounts compared with T1. CONCLUSION: The delivery of HM AA and DHA is significantly affected by TF, with potential clinical implications. When BF is not tolerated, ACF might represent a feasible alternative to reduce TF-related DHA and AA loss.

Lung ultrasound for the diagnosis of pneumonia in children with acute bronchiolitis.

BACKGROUND: Guidelines currently do not recommend the routine use of chest x-ray (CXR) in bronchiolitis. However, CXR is still performed in a high percentage of cases, mainly to diagnose or rule out pneumonia. The inappropriate use of CXR results in children exposure to ionizing radiations and increased medical costs. Lung Ultrasound (LUS) has become an emerging diagnostic tool for diagnosing pneumonia in the last decades. The purpose of this study was to assess the diagnostic accuracy and reliability of LUS for the detection of pneumonia in hospitalized children with bronchiolitis and to evaluate the agreement between LUS and CXR in diagnosing pneumonia in these patients. METHODS: We enrolled children admitted to our hospital in 2016-2017 with a diagnosis of bronchiolitis and undergone CXR because of clinical suspicion of concomitant pneumonia. LUS was performed in each child by a pediatrician blinded to the patient's clinical, laboratory and CXR findings. An exploratory analysis was done in the first 30 patients to evaluate the inter-observer agreement between a pediatrician and a radiologist who independently performed LUS. The diagnosis of pneumonia was established by an expert clinician based on the recommendations of the British Thoracic Society guidelines. RESULTS: Eighty seven children with bronchiolitis were investigated. A final diagnosis of concomitant pneumonia was made in 25 patients. Sensitivity and specificity of LUS for the diagnosis of pneumonia were 100% and 83.9% respectively, with an area under-the-curve of 0.92, while CXR showed a sensitivity of 96% and specificity of 87.1%. When only consolidation > 1 cm was considered consistent with pneumonia, the specificity of LUS increased to 98.4% and the sensitivity decreased to 80.0%, with an area under-the-curve of 0.89. Cohen's kappa between pediatrician and radiologist sonologists in the first 30 patients showed an almost perfect agreement in diagnosing pneumonia by LUS (K 0.93). CONCLUSIONS: This study shows the good accuracy of LUS in diagnosing pneumonia in children with clinical bronchiolitis. When including only consolidation size > 1 cm, specificity of LUS was higher than CXR, avoiding the need to perform CXR in these patients. Added benefit of LUS included high inter-observer agreement. TRIAL REGISTRATION: Identifier: NCT03280732 . Registered 12 September 2017 (retrospectively registered).

Bronchopulmonary dysplasia-impact of severity and timing of diagnosis on neurodevelopment of preterm infants: a retrospective cohort study.

OBJECTIVE: To assess the contribution of the severity of bronchopulmonary dysplasia (BPD) and the time point of its diagnosis to the prediction of neurodevelopmental impairment (NDI) at corrected age of 2 years in preterm infants. DESIGN: Retrospective cohort study. SETTING: Level-III perinatal centre. PATIENTS AND OUTCOME MEASURES: Infants born in 2000-2013 with gestational age <30 weeks. BPD was defined as FiO2 >21% for ≥28 days and its severity classified as mild, FiO2=21%; moderate, FiO2 <30% and severe, FiO2 ≥30% and/or positive pressure support. We applied these criteria at two time points: 36 and 40 weeks' postmenstrual age (PMA). Multivariable regression models were used to estimate the association (OR (95% CI)) between BPD characteristics and NDI defined as cognitive or motor development score <2 SD; severe cerebral palsy; deafness and blindness. RESULTS: Of 610 (81% of cohort) children assessed at 2 years, 357 (58%) had BPD and 98 (16%) had NDI. Neither FiO2 >21% for ≥28 days nor mild or moderate BPD at either 36 or 40 weeks' PMA was associated with NDI, but severe BPD was (at 36 weeks' PMA 5.6 (2.0 to 16.0) and at 40 weeks' PMA 16.6 (4.6 to 59.9)). Infants with severe BPD at both 36 and 40 weeks' PMA had lower mental (mean difference -11.4 (-18.5 to -4.3), -25.7(-35.9 to -15.5), respectively) and motor (-7.8 (-14.9 to -0.6), -20.1(-30.7 to -9.5), respectively), developmental scores than infants without BPD. CONCLUSION: In this cohort, severe BPD was a better independent predictor of NDI at 2 years than mild or moderate BPD. BPD diagnosed at 40 weeks' PMA might allow better identification of infants at highest risk for NDI.

Maternal Supplementation With Krill Oil During Breastfeeding and Long-Chain Polyunsaturated Fatty Acids (LCPUFAs) Composition of Human Milk: A Feasibility Study.

Background: Docosahexaenoic acid (DHA) is a major constituent of neuronal and retinal membranes and plays a crucial role in brain and visual development within the first months of life. Dietary intakes are fundamental to provide neonates with adequate DHA supply; hence, maternal supplementation might represent a useful strategy to implement DHA contents in breast milk (BM), with possible benefits on neonatal neurodevelopment. Antarctic krill is a small crustacean rich in highly available phospholipid-bound DHA. This pilot study aimed to evaluate whether maternal supplementation with krill oil during breastfeeding increases long-chain polyunsaturated fatty acids (LCPUFAs) BM contents. Methods: Mothers of infants admitted to the Neonatal Intensive Care Unit were enrolled in this open, randomized-controlled study between 4 and 6 weeks after delivery and randomly allocated in 2 groups. Group 1 received an oral krill oil-based supplement providing 250 mg/day of DHA and 70 mg/day of eicosapentaenoic acid (EPA) for 30 days; group 2 served as control. BM samples from both groups were collected at baseline (T0) and day 30 (T1) and underwent a qualitative analysis of LCPUFAs composition by gas chromatography/mass spectrometry. Results: Sixteen breastfeeding women were included. Of these, 8 received krill-oil supplementation and 8 were randomized to the control group. Baseline percentage values of DHA (%DHA), arachidonic acid (%AA), and EPA (%EPA) did not differ between groups. A significant increase in %DHA (T0: median 0.23% [IQR 0.19;0.38], T1:0.42% [0.32;0.49], p 0.012) and %EPA (T0: median 0.10% [IQR 0.04;0.11], T1:0.11% [0.04;0.15], p 0.036) and a significant reduction in %AA (T0: median 0.48% [IQR 0.42;0.75], T1:0.43% [0.38;0.61], p 0.017) between T0 and T1 occurred in Group 1, whereas no difference was seen in Group 2. Consistently, a significant between-group difference was observed in percentage changes from baseline of DHA (Δ%DHA, group 1: median 64.2% [IQR 27.5;134.6], group 2: -7.8% [-12.1;-3.13], p 0.025) and EPA (Δ%EPA, group 1: median 39% [IQR 15.7;73.4]; group 2: -25.62% [-32.7;-3.4], p 0.035). Conclusions: Oral krill oil supplementation effectively increases DHA and EPA contents in BM. Potential benefits of this strategy on brain and visual development in breastfed preterm neonates deserve further evaluation in targeted studies. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03583502.

Octreotide in a Critically Ill Extremely Preterm Infant With Perforated Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is the most severe gastrointestinal complication of prematurity. Surgery, either peritoneal drainage placement or laparotomy with resection of the intestinal necrotic tracts, is the definitive treatment of perforated NEC; however, when clinical conditions contraindicate surgical approaches, little is known about medical treatments adjuvant or alternative to surgery. Octreotide is a synthetic somatostatin analog that inhibits pancreatic secretion and leads to splanchnic vasoconstriction. In preterm neonates, it is mainly used off-label for chylothorax and congenital hyperinsulinism, whereas gastrointestinal indications are limited. We describe the case of a critically ill extremely low birth weight infant with perforated NEC, who had unsuccessfully undergone peritoneal drainage placement and laparotomy. Her unstable condition contraindicated a further laparotomy, thus off-label treatment with octreotide was attempted. No adverse events occurred. The infant's condition gradually improved and progressive reduction of peritoneal outputs and successful resolution of pneumoperitoneum were achieved, with no relapse after octreotide discontinuation.

Altered Intracellular ATP Production by Activated CD4+ T-Cells in Very Preterm Infants.

Background. The neonatal immune system is not fully developed at birth; newborns have adequate lymphocytes counts but these cells lack function. Objective. To assess the activity of T-cells and the influence of the main perinatal factors in very preterm infants (birth weight < 1500 g). Design. Blood samples from 59 preterm infants (21/59 were dizygotic twins) were collected at birth and at 30 days of life to measure CD4+ T-cell activity using the ImmuKnow™ assay. Fifteen healthy adults were included as a control group. Results. CD4+ T-cell activity was lower in VLBW infants compared with adults (p < 0.001). Twins showed lower immune activity compared to singletons (p = 0.005). Infants born vaginally showed higher CD4+ T-cell activity compared to those born by C-section (p = 0.031); infants born after prolonged Premature Rupture of Membranes (pPROM) showed higher CD4+ T-cell activity at birth (p = 0.002) compared to infants born without pPROM. Low CD4+ T-cell activity at birth is associated with necrotizing enterocolitis (NEC) in the first week of life (p = 0.049). Conclusions. Preterm infants show a lack in CD4+ T-cell activity at birth. Perinatal factors such as intrauterine inflammation, mode of delivery, and zygosity can influence the adaptive immune activation capacity at birth and can contribute to exposing these infants to serious complications such as NEC.

Respiratory syncytial virus infections in infants affected by primary immunodeficiency.

Primary immunodeficiencies are rare inherited disorders that may lead to frequent and often severe acute respiratory infections. Respiratory syncytial virus (RSV) is one of the most frequent pathogens during early infancy and the infection is more severe in immunocompromised infants than in healthy infants, as a result of impaired T- and B-cell immune response unable to efficaciously neutralize viral replication, with subsequent increased viral shedding and potentially lethal lower respiratory tract infection. Several authors have reported a severe clinical course after RSV infections in infants and children with primary and acquired immunodeficiencies. Environmental prophylaxis is essential in order to reduce the infection during the epidemic season in hospitalized immunocompromised infants. Prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV F protein, is currently recommended in high-risk infants born prematurely, with chronic lung disease or congenital heart disease. Currently however the prophylaxis is not routinely recommended in infants with primary immunodeficiency, although some authors propose the extension of prophylaxis to this high risk population.

Role of cerebral ultrasound and magnetic resonance imaging in newborns with congenital cytomegalovirus infection.

PURPOSE: To assess the diagnostic and prognostic value of cerebral magnetic resonance imaging (cMRI) in comparison with that of cerebral ultrasound (cUS) in predicting neurodevelopmental outcome in newborns with congenital cytomegalovirus (CMV) infection. METHODS: Forty CMV-congenitally infected newborns underwent cUS and cMRI within the first month of life. Clinical course, laboratory findings, visual/hearing function and neurodevelopmental outcome were documented. RESULTS: Thirty newborns showed normal cMRI, cUS and hearing/visual function in the first month of life; none showed CMV-related abnormalities at follow-up. Six newborns showed pathological cMRI and cUS findings (pseudocystis, ventriculomegaly, calcifications, cerebellar hypoplasia) but cMRI provided additional information (white matter abnormalities in three cases, lissencephaly/polymicrogyria in one and a cyst of the temporal lobe in another one); cerebral calcifications were detected in 3/6 infants by cUS but only in 2/6 by cMRI. Four of these 6 infants showed severe neurodevelopmental impairment and five showed deafness during follow-up. Three newborns had a normal cUS, but cMRI documented white matter abnormalities and in one case also cerebellar hypoplasia; all showed neurodevelopmental impairment and two were deaf at follow-up. One more newborn showed normal cUS and cMRI, but brainstem auditory evoked responses were abnormal; psychomotor development was normal at follow-up. CONCLUSIONS: Compared with cUS, cMRI disclosed additional pathological findings in CMV-congenitally infected newborns. cUS is a readily available screening tool useful in the identification of infected newborns with major cerebral involvement. Further studies with a larger sample size are needed to determine the prognostic role of MRI, particularly regarding isolated white matter lesions.

Lung function outcome at school age in very low birth weight children.

OBJECTIVE: The aim of this study was to assess pulmonary function and its predictors in very low birth weight (birth weight ≤1,500 g) children (VLBWc) with or without bronchopulmonary dysplasia (BPD), born at gestational age ≤32 weeks at a single tertiary center during 1996-1999, after the introduction of surfactant therapy. METHODS: Of the 120 surviving VLBW children, 48 (40%) VLBWc (22 with prior-BPD) at age 8.5 ± 1.0 years and 46 age-matched controls (8.8 ± 1.4 years) born at term, underwent lung function study. RESULTS: Adjusted values (z-score) of forced vital capacity (z-FVC), forced expiratory volume in 1 sec (z-FEV1), forced expiratory flow 25-75% (z-FEF25-75), carbon monoxide lung diffusion capacity (z-DLCO), and DLCO/alveolar volume (z-DLCO/VA) were significantly lower than controls (mean difference, 95% CI: -1.35, -1.81 to -0.90, P < 0.001; -1.31, -1.73 to -0.90, P < 0.001; -0.87, -1.29 to -0.46, P < 0.001; -0.98, -1.72 to -0.23, P < 0.001; -0.70, -1.22 to -0.18, P < 0.05; respectively). Residual volume (z-RV) and RV/total lung capacity (RV/TLC) ratio (%) were significantly higher in VLBWc than controls (mean difference, 95% CI: 1.06, 0.44 to 1.68, P < 0.001; 9.54%, 5.73 to 13.3%, P < 0.001; respectively). No differences were found in lung function between VLBWc (no-BPD vs. BPD) with the exception of a significant higher RV/TLC ratio in the BPD-subgroup (mean difference, 95% CI: 7.0%, 0.4 to 13%, P = 0.03). Lung function abnormalities were found in 30 (63%) VLBWc with evidence of airway obstruction and diffusing capacity impairment. A weak relationship was observed between gestational age with z-FVC (r = 0.30, P = 0.04), birth weight with z-FEV1 (r = 0.30, P = 0.04) and RV/TLC ratio (r = -0.49, P = 0.001). The duration of oxygen treatment correlated negatively with the z-DLCO/Va (r = -0.5, P = 0.02). No differences were found in FeNO levels between VLBWc and controls. CONCLUSION: VLBWc at school age showed lung function abnormalities characterized by airway obstruction, hyperinflation, and diffusion impairment. Neonatal lung damage together with preterm birth may play a role in worsening the functional respiratory outcome.

Longitudinal trajectories of gestural and linguistic abilities in very preterm infants in the second year of life.

The present study involved a systematic longitudinal analysis, with three points of assessment in the second year of life, of gestures/actions, word comprehension, and word production in a sample of very preterm infants compared to a sample of full-term infants. The relationships among these competencies as well as their predictive value on language development at 24 months and the contribution of biological, medical and social risk factors on language delay at 24 months were also analysed. One hundred and four monolingual Italian very preterms (mean gestational age 29.5 weeks) without major cerebral damages, and a comparison group of 20 monolingual healthy Italian full-terms were followed at 12, 18 and 24 months by administering to their parents the Italian short forms of the MacArthur-Bates CDI. Preterms showed a slower acquisition in gesture/action production, word comprehension, and word production with an increasing divergence with respect to full-terms from 12 to 24 months, when 20% of preterms were delayed in word production (<10th percentile) and 14% did not combine words yet. Lexical competencies at 12 months and together with gestures/actions at 18 months were predictive of word production at 24 months, with a stronger contribution of word comprehension at 12 months and of word production at 18 months. Male gender, bronchopulmonary dysplasia, and low maternal educational level increased the risk of language delay at 24 months. Our findings suggest there to be a slower rate of communicative-linguistic development in very preterms with an increasing difference in their gestural and lexical competencies in the second year of life with respect to full-terms. The interplay of the above competencies and biological, medical and social risk factors increase the risk of language delay at 24 months in very preterm infants.

Urinary neutrophil gelatinase-associated lipocalin at birth predicts early renal function in very low birth weight infants.

Preterm infants are exposed to conditions that can impair renal function. We evaluated the ability of serum and urinary neutrophil gelatinase-associated lipocalin (sNGAL and uNGAL) to predict renal function in the first weeks of life. From September 2008 to July 2009, infants weighing ≤1500 g at birth with no major congenital anomalies or sepsis were eligible. We measured sNGAL and uNGAL levels at birth. To evaluate renal function, we determined changes in serum creatinine (sCreat) and estimated GFR (eGFR) from birth to d 21. Forty neonates (mean GA, 27 ± 2 wk) completed the study. Renal function improved in 32 of 40 (80%) infants (normal renal function, NRF group) (sCreat, from 0.97 ± 0.2 to 0.53 ± 0.13 mg/dL; eGFR, from 15.3 ± 4.1 to 28.6 ± 7.9 mL/min), whereas renal function worsened in 8 of 40 (20%) infants (impaired renal function, IRF group) (sCreat, from 0.71 ± 0.27 to 0.98 ± 0.43 mg/dL; eGFR from 23 ± 14.7 to 16.4 ± 9.1 mL/min). The uNGAL/urinary creatinine (uCreat) ratio at birth was higher in the IRF group (31.05 ng/mg) than the NRF group (6.0 ng/mg), and uNGAL was significantly higher in IRF group, detecting IRF with a cutoff of 100 ng/mL. uNGAL levels at birth may have a predictive role in very LBW (VLBW) infants.

Adapting a Vacuum Assisted Closure dressing to challenging wounds: negative pressure treatment for perineal necrotizing fasciitis with rectal prolapse in a newborn affected by acute myeloid leukaemia.

We report the case of a newborn with acute myeloid leukaemia, who developed perineal necrotizing fasciitis due to Pseudomonas Aeruginosa, after twenty days of life. Following surgical debridement, she was effectively treated with topical negative pressure therapy (V.A.C.(R) device) with silver foam dressings, this achieved complete closure in thirteen days. Negative pressure therapy should be considered when conventional wound care fails to achieve complete wound closure, even in neonates.

Very low birth weight infants born to cytomegalovirus-seropositive mothers fed with their mother's milk: a prospective study.

OBJECTIVE: To assess the risk of post-natal cytomegalovirus (CMV) transmission to very low birth weight (VLBW) infants fed with their mother's fresh milk. STUDY DESIGN: Prospective, observational study of 80 VLBW infants and their 68 mothers. Infants' urine and their own mother's fresh breast milk were tested for CMV by means of culture tests once a week until discharge. CMV in infected milk and urine were genotyped. The clinical course, laboratory findings, and outcome of infants infected with CMV at 2 years of age are reported. RESULTS: Fifty-three mothers (78%) were CMV-seropositive at delivery. CMV was detected in the milk of 21 of 53 seropositive mothers (40%), and CMV was in the urine in 9 of 26 infants (35%) fed with CMV-positive milk. The same gN-genotype was found in milk and urine. Three infected infants <28 weeks gestational age (GA) had a mild sepsis-like illness. Five more infants had neutropenia, conjugated hyperbilirubinaemia, or both. Post-natal CMV infection occurred in 1 of 19 infants with a GA<28 weeks who were treated at birth with intravenous immunoglobulin versus 3 of 5 non-treated infants (P < .02). Symptomatic CMV infection was associated with bronchopulmonary dysplasia. No neurosensorial sequelae were found at 2 years of corrected age. CONCLUSIONS: CMV infection via fresh human milk is mild, self-limiting, and without sequelae. Very-low GA and pre-existing chronic diseases are associated with symptomatic infection.