Fate of melatonin orally administered in preterm newborns: Antioxidant performance and basis for neuroprotection.

Preterm infants cannot counteract excessive reactive oxygen species (ROS) production due to preterm birth, leading to an excess of lipid peroxidation with malondialdehyde (MDA) production, capable of contributing to brain damage. Melatonin (ME), an endogenous brain hormone, and its metabolites, act as a free radical scavenger against ROS. Unfortunately, preterms have an impaired antioxidant system, resulting in the inability to produce and release ME. This prospective, multicenter, parallel groups, randomized, double-blind, placebo-controlled trial aimed to assess: (i) the endogenous production of ME in very preterm infants (gestational age ≤ 29 + 6 WE, 28 infants in the ME and 26 in the placebo group); (ii) the exogenous hormone availability and its metabolization to the main metabolite, 6-OH-ME after 15 days of ME oral treatment; (iii) difference of MDA plasma concentration, as peroxidation marker, after treatment. Blood was collected before the first administration (T1) and after 15 days of administration (T2). ME and 6-OH-ME were detected by liquid chromatography tandem mass spectrometry, MDA was measured by liquid chromatograph with fluorescence detection. ME and 6-OH-ME were not detectable in the placebo group at any study time-point. ME was absent in the active group at T1. In contrast, after oral administration, ME and 6-OH-ME resulted highly detectable and the difference between concentrations T2 versus T1 was statistically significant, as well as the difference between treated and placebo groups at T2. MDA levels seemed stable during the 15 days of treatment in both groups. Nevertheless, a trend in the percentage of neonates with reduced MDA concentration at T2/T1 was 48.1% in the ME group versus 38.5% in the placebo group. We demonstrated that very preterm infants are not able to produce endogenous detectable plasma levels of ME during their first days of life. Still, following ME oral administration, appreciable amounts of ME and 6-OH-ME were available. The trend of MDA reduction in the active group requires further clinical trials to fix the dosage, the length of ME therapy and to identify more appropriate indexes to demonstrate, at biological and clinical levels, the antioxidant activity and consequent neuroprotectant potential of ME in very preterm newborns.

Preterm Newborn Adaptive Responses to Daily Nursing during Neonatal Intensive Care Unit Stay, Associate with Neurodevelopment, 2 Years Later.

OBJECTIVE: This study aimed to evaluate if adaptive responses of very preterm newborns to neonatal intensive care unit (NICU) daily nursing, specifically bathing and weighing procedures are associated with their neurodevelopment after 2 years. STUDY DESIGN: Twenty-six very preterm newborns, with a gestational age <32 weeks, were enrolled. Infants' adaptive responses to daily nursing were evaluated, at 30 to 32 to 35 postmenstrual age (PMA) weeks by an observational sheet. Neurodevelopment was assessed at 24 months of corrected age by the Bayley Scales of Infant and Toddler Development, third edition. Autonomic, motor, and self-regulatory responses to NICU nursing were analyzed by Spearman's correlation coefficient and multivariate linear regression with Bayley's cognitive, language, and motor scales. RESULTS: Significant (p < 0.05) positive correlations of self-regulatory and autonomic responses to nursing with all Bayley's scales were found at 30- and 32-week PMA. At 35-week PMA, only self-regulatory responses had significant positive correlations with all Bayley's scales. When adjusted for birth weight and sex, the significant associations were confirmed only at 30- and 32-week PMA. CONCLUSION: Very preterm newborn adaptive responses to NICU daily nursing reveal to be positively related to forthcoming neurodevelopment 2 years later, as early as the 30-week PMA. Helping preterm babies to adapt to daily NICU nursing may promote their future neurobehavior. KEY POINTS: · Preterm adaptation to nursing was studied.. · Adaptation positively relates to neurodevelopment.. · Such relation is detected since 30-week PMA..

Chorionicity, birth weight discordance and neonatal morbidity in uncomplicated twin pregnancies delivered from 36 weeks.

OBJECTIVES: To investigate the association between chorionicity, birth weight discordance and neonatal morbidity in uncomplicated twin pregnancies progressing to at least 36 weeks of gestation. STUDY DESIGN: This was a retrospective single centre cohort study of all twin pregnancies referred to our twin clinic between 2011 and 2018. Outcome details were obtained from the computerized maternity and neonatal records. The primary outcome was incidence of composite neonatal morbidity according to chorionicity. We also determined the incidence of composite neonatal morbidity in pregnancies with birth weight discordance. Logistic regression was used to identify and adjust for potential confounders. RESULTS: Three hundred and eighty-five twin pregnancies (286 dichorionic, 99 monochorionic) were included. Gestational age at birth was significantly lower in pregnancies complicated by neonatal morbidity (p = 0.013) compared with those which were not. On multivariable logistic regression analysis, gestational age at birth (p = 0.031) and birth weight discordance (p = 0.004), but not chorionicity (p = 0.626) were independently associated with neonatal morbidity. CONCLUSION(S): In uncomplicated twin pregnancies chorionicity is not associated with neonatal morbidity. Gestational age at birth is the major determinant of neonatal outcome while the clinical impact of weight discordance seems marginally significant.

Neurodevelopment of infant with late fetal growth restriction.

Late fetal growth restriction has increasingly gain interest. Differently from early fetal growth restriction, the severity of this condition and the impact on perinatal mortality and morbidity is less severe. Nevertheless, there is some evidence to suggest that fetuses exposed to growth restriction late in pregnancy are at increased risk of neurological dysfunction and behavioral impairment. The aim of our review was to discuss the available evidence on the neurodevelopmental outcome in fetuses exposed to growth restriction late in pregnancy. Cerebral blood flow redistribution, a Doppler hallmark of late fetal growth restriction, has been associated with this increased risk, although there are still some controversies. Currently, most of the available studies are heterogeneous and do not distinguish between early and late fetal growth restriction when evaluating the long-term outcome, thus, making the correlation between late fetal growth restriction and neurological dysfunction difficult to interpret. The available evidence suggests that fetuses exposed to late growth restriction are at increased risk of neurological dysfunction and behavioral impairment. The presence of the cerebral blood flow redistribution seems to be associated with adverse neurodevelopmental outcome, however, from the present literature the causality cannot be ascertained.

Group B Streptococcus late onset sepsis in very low birth weight newborns: 10 years experience.

PURPOSE: The incidence of late-onset neonatal infection (LONS) group B streptococcus (GBS) in very low birth weight (VLBW) is still matter of debate. In the present 10-years retrospective study we investigated the epidemiology of GBS LONS in VLBW neonates. MATERIALS AND METHODS: From January 2006 to July 2015 we conducted a retrospective study in all preterm infants admitted at our third level referral center for neonatal intensive care (NICU). From our database we were able to retrieve all cases of bloodstream infections/meningitis GBS positive. Perinatal data were also collected Results: On a total of 13 747 infants 975 (7%) were VLBW and in seven cases of GBS LONS was observed with a incidence of 7.2/1000 live births. CONCLUSIONS: The higher rate of LONS GBS in our series offer additional support to further investigations in wider population in order to better define GBS screening and therapeutic management in a such specific population.

Performance of 1,3-ß-D-glucan for diagnosing invasive fungal diseases in children.

Plasma 1,3-ß-D-glucan (BDG) is indicated as a tool for early diagnosis of invasive fungal diseases (IFD). However, data on its diagnostic value are scarce in children. Therefore, definition of BDG test performance in paediatrics is needed. BDG was evaluated in children admitted to "Istituto Giannina Gaslini," Genoa, Italy, who developed clinical conditions at risk for IFD. Results were analysed for sensitivity, specificity, predictive values, likelihood ratios, accuracy, informedness and probability of missing one case by a negative test. A total of 1577 BDG determinations were performed on 255 patients (49% males, median age 5.4 years). Overall 46 IFD were diagnosed, 72% proven/probable. The test performance was evaluated for 80 pg/mL, 120 pg/mL, 200 pg/mL, 350 pg/mL, 400 pg/mL cut offs. Sensitivity was always <0.80 and specificity > 0.90 only for cut offs ≥200 pg/mL. Negative predictive value was ≥0.90 for all the cut offs evaluated, while positive predictive value resulted barely 0.50 (8% IFD prevalence). Accuracy was never >0.90, and informedness was at best 0.50. The risk of missing one IFD by a negative result was < 10%. Analyses in haemato-oncological or newborn patients did not show major differences. Detection of serum BDG does not appear a valuable adjunctive diagnostic tool for IFD in paediatrics.

A retrospective analysis of the occurrence of accidents during 20 years of neonatal transport in Liguria region, Italy.

Our article focuses on a retrospective analysis of the occurrence of accidents relating to 20 years of activity of Neonatal Emergency Transport Service (NETS) in Liguria region, Italy. The objective of this study is to determine the vehicle accident rate for a specialized emergency medical services-NETS transport system between 1995 and 2015. We reviewed 5035 medical records related to the activity of our NETS from its beginning, in February 1995 to June 2015. We identified the occurrence of three road accidents (rate ∼1 : 1600 transports; 1 : 170 000 driven km), no helicopter accidents and only one technical problem during helicopter use; our service was not involved in any crashes resulting in injury. We discussed some reasons possibly explaining these good results.

Candida infections in paediatrics: Results from a prospective single-centre study in a tertiary care children's hospital.

To describe the epidemiology of invasive Candida infection in a tertiary care paediatric hospital. Prospective single-centre survey on all Candida strains isolated from normally sterile fluids and urines in the period 2005-2015 . A total of 299 ICI were documented in 262 patients. Urinary tract infection represented the most frequent diagnosis (62%), followed by fungaemia (34%) and peritonitis (4%). Fungaemia was most frequent in children with cancer (59%) or in low birth weight neonates (61%), while urinary tract infections were more frequent in patients with urinary tract malformation. C.albicans was the most frequently isolated species (60%) compared with C. non-albicans, but differences were present according to the site of isolation and underlying conditions. Overall 90-day mortality was 7%, 13% in fungaemias, 8% in peritonitis and 2% in urinary tract infections. The rates of invasive Candida infection increased during the study period. Invasive Candida infection is diagnosed with increasing frequency in children. Site of isolation and aetiology are frequently related with the presence of underlying, favouring conditions. Mortality was not negligible, especially in the presence of more invasive infections and specific underlying conditions.

Neurological abnormalities in full-term asphyxiated newborns and salivary S100B testing: the "Cooperative Multitask against Brain Injury of Neonates" (CoMBINe) international study.

BACKGROUND: Perinatal asphyxia (PA) is a leading cause of mortality and morbidity in newborns: its prognosis depends both on the severity of the asphyxia and on the immediate resuscitation to restore oxygen supply and blood circulation. Therefore, we investigated whether measurement of S100B, a consolidated marker of brain injury, in salivary fluid of PA newborns may constitute a useful tool for the early detection of asphyxia-related brain injury. METHODS: We conducted a cross-sectional study in 292 full-term newborns admitted to our NICUs, of whom 48 suffered PA and 244 healthy controls admitted at our NICUs. Saliva S100B levels measurement longitudinally after birth; routine laboratory variables, neurological patterns, cerebral ultrasound and, magnetic resonance imaging were performed. The primary end-point was the presence of neurological abnormalities at 12-months after birth. RESULTS: S100B salivary levels were significantly (P<0.001) higher in newborns with PA than in normal infants. When asphyxiated infants were subdivided according to a good (Group A; n = 15) or poor (Group B; n = 33) neurological outcome at 12-months, S100B was significantly higher at all monitoring time-points in Group B than in Group A or controls (P<0.001, for all). A cut-off >3.25 MoM S100B achieved a sensitivity of 100% (CI5-95%: 89.3%-100%) and a specificity of 100% (CI5-95%: 98.6%-100%) as a single marker for predicting the occurrence of abnormal neurological outcome (area under the ROC curve: 1.000; CI5-95%: 0.987-1.0). CONCLUSIONS: S100B protein measurement in saliva, soon after birth, is a useful tool to identify which asphyxiated infants are at risk of neurological sequelae.

Urine S100 BB and A1B dimers are valuable predictors of adverse outcome in full-term asphyxiated infants.

AIM: To investigate whether S100A1B and BB dimers are predictors of early perinatal death in newborns with perinatal asphyxia (PA). METHODS: The study compared 38 full-term newborns with PA [neonatal death n = 11; hypoxic ischaemic encephalopathy (HIE): n = 27] with a control group of 38 healthy infants. Clinical and laboratory parameters were recorded at eight time points and urine collected for S100B assessment. Multivariate analysis was performed in order to analyse the influence of various clinical parameters on the occurrence of neonatal death. RESULTS: A1B and BB in PA nonsurvivor infants were significantly higher (p < 0.001) than in controls at all monitoring time points. BB at first void (cut-off>42 ng/L) was the best predictor of early neonatal death (p < 0.05) of all the clinical and laboratory parameters studied. CONCLUSION: These results suggest that S100s are valuable predictors of adverse outcome in PA infants. It is also suggested that these biomarkers be used in daily clinical practice, due to their low cost and stress, reproducibility and the possibility of longitudinal monitoring.

Biomarkers of brain damage in preterm infants.

OBJECTIVE: There is growing evidence on the usefulness of biomarkers in the early detection of preterm infants at risk for brain damage. However, among different tools Activin A, S100B protein and adrenomedullin assessment offer the possibility to investigate brain/multiorgan function and development. This could be especially useful in perinatal medicine that requires even more non-invasive techniques in order to fulfill the minimal handling in diagnostic and therapeutic strategy performance. MATERIALS AND METHODS: The concept of Unconventional Biological Fluid (UBF: urine and saliva) is becoming even stronger and regards the assessment in non-invasive biological fluids of biochemical markers involved in the cascade of events leading to brain damage. RESULTS: Activin A, S100B protein and adrenomedullin in UBF were increased in preterm newborns developing brain damage and/or ominous outcome. CONCLUSIONS: The present manuscript offers an update on the usefulness of Activin A, S100B protein an adrenomedullin in UBF as brain damage markers. The findings open a new cue on the use of these markers in daily neonatal intensive care unit (NICU) activities.

Preterm and term newborn: primary investigations.

The present overview is aimed at reporting the standard primary investigations that are mandatory in preterm and term newborns at admission to neonatal unit in the first hours after birth. Herein, the main neonatal screening tests for early detection of metabolic diseases are described as well as laboratory standard procedures (glycaemia, bilirubin, blood gas, infectious diseases analyses) monitoring parameters (vital signs recordings, blood and transcutaneous gas assessment, blood pressure recordings) and ultrasound pattern (cranial and cardiac).

Perinatal asphyxia: kidney failure does not affect S100B urine concentrations.

BACKGROUND: S100B protein is a well-established marker of brain damage. Its importance in urine assessment is the convenience of a collection and sampling procedure that can be repeated without risk for the newborn. Since S100B is mainly eliminated by the kidneys and perinatal asphyxia (PA) is often associated with kidney failure we investigated whether S100B release might be kidney-mediated, thereby modifying the protein's reliability as a brain-damage marker. METHODS: We examined a cohort of healthy (n=432) and asphyxiated newborns (n=32) in whom kidney function parameters (blood urea and creatinine concentrations and urine gravity) and urine S100B concentrations were assessed in the first hours after birth. Data were analyzed by multiple logistic regression analysis with S100B as independent variable among a variety of clinical and laboratory monitoring parameters. RESULTS: S100B urine concentrations were significantly higher (P<0.01) in PA newborns than controls. No significant correlations (P>0.05, for all) between total urine S100B levels and kidney function parameters such as creatinine (r=0.03), urea (r=0.04) and urine gravity (r=0.06) were found. Multiple logistic regression analysis of a series of clinical and laboratory monitoring parameters (odds ratio at sampling: 9.47) with S100B as independent variable showed a positive significant correlation only between S100B levels (P<0.001) and the occurrence of PA. CONCLUSION: The present study shows that altered kidney function is not an adverse and/or confounding factor in urine S100B assessment and marks a new step towards the introduction of longitudinal monitoring of brain constituents in clinical practice.

Italia-Netherland PhD Program: the I.O. PhD Research Program.

In the framework of long-term scientific collaboration among the founder members coming from Holland and Italy there was a growing consensus to activate a philosophical doctorate (PhD) program, involving young Italian researchers in the field of perinatal medicine, neonatology and pediatrics. The aims were to promote excellence in research, offering to young Italian physicians the opportunity to maturate an International research experience leading to PhD degree, and to promote human and technological improvement energies in perinatal, neonatal and pediatrics research. Thus, an official collaboration among the Dutch Universities from Maastricht and Utrecht and the Italian Children's Hospital from Alessandria, has been activated on March 1st 2010, finalized to the PhD program. The experimental phase included the selection of projects and relative candidates after an interview-selection focusing on their scientific attitudes and the availability on their research projects. Candidates' selection started on May 2010 and on September 29th ten projects and candidates have been approved by the scientific commission. Research topics included: perinatal asphyxia, aging and the origin of adulthood neurodegenerative disease, neuroprotective strategies, biochemical pulmonology, intrauterine growth retardation and perinatal teratology. To date, all projects have been approved by local Ethics Committee from the University/Hospital of origin of the candidates. Five manuscripts have been published and/or submitted to international Journals regarding pneumology, perinatal asphyxia and teratology, whilst about 60-70% of data regarding clinical studies have already been collected.

Antenatal glucocorticoid treatment affects preterm infants' S100B urine concentration in a dose-dependent manner.

BACKGROUND: Maternal glucocorticoid (GC) treatment is widely used to prevent lung immaturity in preterm infants. There is growing evidence that GCs may be detrimental to the Central Nervous System (CNS). We investigated whether antenatal GC administration affects CNS function in a dose-dependent manner by measuring urine concentrations of a well-established brain damage marker, S100B. METHODS: We conducted a case-control-study in 70 preterm infants (1 GC vs 1 control) whose mothers received a complete GC-course (GC2, n=16), half-course (GC1, n=19), and controls (n=35). At four predetermined time-points, in the first 72 h from birth, we assessed S100B urine concentrations, using a commercially available immunoluminometric assay (Lia-mat Sangtec 100, AB Sangtec Medical, Bromma, Sweden). Data were correlated with primary neonatal outcomes (incidence of respiratory distress syndrome, length of ventilatory support and hospital stay, incidence of intraventricular hemorrhage, adverse 7th day neurological follow-up and neonatal death). RESULTS: S100B in GC2 group at all monitoring time-points was significantly lower (P<0.01) than controls and GC1 group, while no differences (P>0.05) were evident between controls and GC1 group. No significant differences (P>0.05) were shown in primary outcomes between half or complete GC-course treated groups. CONCLUSION: S100B levels of infants antenatally treated with GCs differed in a dose-dependent manner. Data on primary outcomes suggest that lowering antenatal GC-course may be less detrimental for brain without affecting lung maturation. Further clinical trials are needed to elucidate the low GC-course issue.

Naturally occurring immune response against bacteria commonly involved in upper respiratory tract infections: analysis of the antigen-specific salivary IgA levels.

Lyophilized bacterial lysates, which actively stimulate the immune response, are widely used as vaccines or 'biological response modifiers' in subjects with recurrent bacterial respiratory infections. Since vaccines are indicated in the absence or in the presence of a weak constitutive immune response activity, a better knowledge on the 'naturally' occurring antibacterial immune response at the oropharingeal level should be helpful. A study was, therefore, designed to quantify the presence of salivary IgA directed against surface antigens bacteria frequently involved in the pathogenesis of upper respiratory tract infections: Klebsiella pneumoniae (KP), Staphylococcus aureus (SA), Streptococcus pyogenes (SPy), Morraxella catarrhalis (MC), Haemophylus influenzae (HI), and Streptococcus pnumoniae (SPn). In 34 volunteers (21 adults and 13 children), salivary fluid was collected and the presence of microorganism-specific IgA antibodies evaluated by a novel enzyme immuno-assay. In the whole population only 29 and 24% of subjects had IgA directed, respectively, to KP and SA, while the immune-response against other microbes was detectable in a small population ranging from 12 to 15% of all subjects studied. We found higher proportions of individuals with strain specific salivary IgA in the adult than in the pediatric population for all the microorganism evaluated. In addition, in children, the only strain inducing a significant production of specific IgA at oropharingeal level was KP. Interestingly, only ten out of 21 adults and two out 13 children have at least one significantly high antibody titer against one of the bacteria evaluated. Nevertheless, when a group of healthy donors was treated with a polyvalent mechanical bacterial lysate (Ismigen t.), the large majority developed a specific immune-response in the salivary fluid. These results are thus consistent with the good features of the novel enzyme-immunoassay and with a poor frequency of naturally induced specific anti-microbe antibodies in children and in adults despite the presence on recurrent respiratory infections in their clinical history.