Neurodevelopmental outcome of preterm very low birth weight infants admitted to an Italian tertiary center over an 11-year period.

Preterm very low birth weight infants (VLBWi) are known to be at greater risk of adverse neurodevelopmental outcome. Identifying early factors associated with outcome is essential in order to refer patients for early intervention. Few studies have investigated neurodevelopmental outcome in Italian VLBWi. The aim of our longitudinal study is to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year cohort of 502 Italian preterm VLBWi and to identify associations with outcome. At 24 months, Griffiths' Mental Developmental Scales were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). 75.3% showed a normal outcome, 13.9% minor sequelae and 10.8% major sequelae (3.8% cerebral palsy). Male gender, bronchopulmonary dysplasia, abnormal neonatal neurological assessment and severe brain ultrasound abnormalities were independently associated with poor outcome on multivariate ordered logistic regression. Rates of major sequelae are in line with international studies, as is the prevalence of developmental delay over cerebral palsy. Analysis of perinatal complications and the combination of close cUS monitoring and neurological assessment are still essential for early identification of infants with adverse outcome.

Early parenting intervention promotes 24-month psychomotor development in preterm children.

AIM: Although parenting is key to promoting healthy development of at-risk preterm infants, parents have often restricted access to neonatal intensive care units (NICUs). This study aimed to assess the effect of an early parenting intervention on the psychomotor outcome in preterm children at 24 months of corrected age. METHODS: Forty-two preterm children and their parents were consecutively recruited at a level III NICU in Northern Italy and randomly allocated to early intervention (two educational peer-group sessions and four individual infant observation sessions) or care as usual (no educational or infant observation sessions). During NICU stay, parents provided information on daily holding and skin-to-skin. Psychomotor development was measured at 24 months of corrected age using the Griffith Mental Development Scales. RESULTS: There were no significant differences in socio-demographic and clinical variables between early intervention (n = 21; 13 females) and care as usual (n = 21; 12 females) groups. At 24 months of corrected age, children in the early intervention arm had greater scores for global psychomotor development as well as for Hearing-Speech and Personal-Social sub-scales, compared to those in the care as usual group. CONCLUSION: The present NICU parenting intervention was found to be associated with better psychomotor outcomes in preterm children at 24-month age. The effects were especially evident for domains related to language and socio-emotional functioning. Results are promising and should be retested with more heterogeneous and representative preterm sample.

Correction to: Probiotics' efficacy in paediatric diseases: which is the evidence? A critical review on behalf of the Italian Society of Pediatrics.

An amendment to this paper has been published and can be accessed via the original article.

Vertical Transmission of SARS-CoV-2 (COVID-19): Are Hypotheses More than Evidences?

In spite of the increasing, accumulating knowledge on the novel pandemic coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), questions on the coronavirus disease-2019 (COVID-19) infection transmission from mothers to fetuses or neonates during pregnancy and peripartum period remain pending and have not been addressed so far. SARS-CoV-2, a RNA single-stranded virus, has been detected in the amniotic fluid, in the cord blood and in the placentas of the infected women. In the light of these findings, the theoretical risk of intrauterine infection for fetuses, or of peripartum infection occurring during delivery for neonates, has a biological plausibility. The extent of this putative risk might, however, vary during the different stages of pregnancy, owing to several variables (physiological modifications of the placenta, virus receptors' expression, or delivery route). This brief review provides an overview of the current evidence in this area. Further data, based on national and international multicenter registries, are needed not only to clearly assess the extent of the risk for vertical transmission, but also to ultimately establish solid guidelines and consistent recommendations. KEY POINTS: · Questions on the COVID-19 infection transmission from mothers to fetuses or neonates during pregnancy and peripartum period remain pending so far.. · The theoretical risk of intrauterine infection for fetuses, or of neonatal infection during delivery for neonates, has a biological plausibility.. · A caution is recommended in the interpretation of clinical and laboratory data in neonates..

Probiotics' efficacy in paediatric diseases: which is the evidence? A critical review on behalf of the Italian Society of Pediatrics.

During the last decade several paediatric studies have been published with different possible indications for probiotics, leading to a global increase of probiotics' market. Nevertheless, different study designs, multiple single/combined strains and small sample size still leave many uncertainties regarding their efficacy. In addition, different regulatory and quality control issues make still very difficult the interpretation of the clinical data. The objective of this review is to critically summarise the current evidence on probiotics' efficacy and safety on a different number of pathologies, including necrotizing enterocolitis, acute infectious diarrhoea, allergic diseases and functional gastrointestinal disorders in order to guide paediatric healthcare professionals on using evidence-based probiotics' strains. To identify relevant data, literature searches were performed including Medline-PubMed, the Cochrane Library and EMBASE databases. Considering probiotics strain-specific effects, the main focus was on individual probiotic strains and not on probiotics in general.

Neonatal vesiculopustular eruption in Down syndrome and transient myeloproliferative disorder: A case report and review of the literature.

Transient myeloproliferative disorder (TMD) is a spontaneously resolving clonal myeloid proliferation characterized by circulating megakaryoblasts in the peripheral blood that is restricted to neonates with Down syndrome (DS) or those with trisomy 21 mosaicism. Cutaneous manifestations of TMD are observed in only 5% of affected neonates and present as a diffuse eruption of erythematous, crusted papules, papulovesicles, and pustules, often with prominent and initial facial involvement. We describe the case of a male infant with DS and TMD, associated with a vesiculopustular eruption, which appeared on day 36 of life, and review previous cases.

Anomalous Fusion of Right Pulmonary Artery to Aortic Arch: Case Report of a Rare and Fatal Congenital Malformation in a Newborn and a Literature Review.

BACKGROUND We present a report of a rare cardiac malformation case as well as a review of the literature. In addition, the diagnostic features are discussed. CASE REPORT The case of a female newborn who died on her third day of life was studied at the Institute of Legal Medicine, University of Chieti-Pescara (Italy). The investigations around her death revealed a cardiac congenital malformation, seen as a rare variant of a common arterial trunk, in which the aorta was fused with the right branch of the pulmonary artery. The ascending aorta showed hypoplasia, while the coronary arteries were free of any pathological findings. The atrial septum showed a closed foramen ovale and the ventricular septum did not show any defect. Only an isolated right ventricular hypertrophy and dilation with no other cardiac abnormalities was found. The cause of death was acute respiratory failure on the third day of extrauterine life when the ductus Botalli closed. The karyotype analysis performed in this case was normal, and the fluorescent in situ hybridization analysis did not show the 22q11.2 microdeletion suggestive of the DiGeorge syndrome. CONCLUSIONS These findings underline the value of 3-dimensional/4-dimensional ultrasound imaging when added to a fetal cardiology screening program, and the need for improvements in postnatal screening routines by using pulse oximetry in order to discover isolated vascular defects before circulatory collapse occurs, as well as to reduce the medico-legal disputes in cases of missed diagnosis. We found the relevant literature search lacked a description of this congenital malformation, which supports our deeper perinatal investigation.

New Diagnostic Possibilities for Neonatal Sepsis.

Progress in neonatal care has decrease morbidity and mortality due to neonatal sepsis (NS). Although diagnosis of sepsis continues to rely on blood culture, this method is too slow and limited by false-negative results. There are numerous sepsis biomarkers that have been evaluated for the early diagnosis of NS, but, to date, there is no single ideal biomarker, though novel biomarkers are becoming more sophisticated and specific in their clinical applications. This review provides an overview of the current diagnostic approaches available or under development for diagnosing NS.

The Mother-Child Relationship during the First Months of Life: Preliminary Considerations in Preterm as Compared with Term Mother-Infant Dyads.

INTRODUCTION: From the prognostic perspective, the quality of the mother-child relationship during the first months of life has been variously associated with different factors such as the child's psychomotor/cognitive development and emotional-behavioral disorders. METHODS: The main aim of this study was to describe, at term age and 3 months of corrected age, the features and the prevalent patterns of the mother-child relationship in a group of 20 mother-preterm infant dyads and to compare them with those of a group of 20 mother-term infant dyads. RESULTS: A relatively high rate of inadequate dyadic synchrony was found in our sample of preterms at 40 weeks of gestational age (half of the sample analyzed). The quality of the dyadic relationship and the prevalent patterns of the mother-child relationship were found to differ between the two groups we studied; moreover, the subjects at risk of relational problems remained substantially the same during the first 3 months of life. DISCUSSION: These data underline that in preterm children, the first weeks of life, coinciding with their hospitalization, represent a crucial time for establishing a valid dyadic relationship and for considering and planning any preventive interventions; after all, the earlier the risk of relational problems becomes a real possibility, the more likely it is to negatively impact on a child's overall development.

Novel Approaches to the Study of Neonatal Infections.

The pathogenesis of neonatal infection is incompletely understood. Neonatal immune immaturity and the microbial factors of virulence only partially explain the interindividual differences in the protective responses to the most common neonatal pathogens. Stratification of infants into high- and low-risk groups through epidemiological studies has been invaluable in designing preventive strategies and reducing the burden of neonatal infection. The discovery of the role of maternal antibodies (Abs) as, for instance, anti-capsular polysaccharide group B streptococcal (GBS) Abs, in protecting newborn infants against neonatal GBS sepsis, has been a milestone in the unraveling of the molecular underpinnings of susceptibility to infection in the neonatal age. Future work should aim at defining the cellular and molecular differences in the neonatal immune responses that account for individual susceptibility and resistance to common neonatal pathogens. The interplay between the genetic and immune backgrounds of the infant, changes in the infant's microbiome, maternal factors, and the pathogen's characteristics needs to be accurately described through human studies. Precise phenotyping and dissection of the clinical heterogeneity of neonatal infection should identify cohorts that can be studied through different study methodologies. Term and preterm infants should be investigated according to the most likely underlying mechanism, single-gene disorders and multifactorial predisposition, respectively. Novel technologies, including genotyping studies, exome and genome sequencing, analysis of the microbiome, and the study of the metabolome, are nowadays established and available and can be integrated to gain a better insight into the unexplained bases of individual susceptibility to neonatal infections.

Characterization of an Outbreak of Extended-Spectrum ß-Lactamase-Producing Klebsiella pneumoniae in a Neonatal Intensive Care Unit in Italy.

Here we report an outbreak of extended spectrum ß-lactamase-producing Klebsiella pneumoniae that occurred in a neonatal intensive care unit in Northern Italy and involved 97 patients. Progressively tightened sets of containment measures were implemented but the epidemic event was stopped only 9 months later. The final, effective, containment strategy consisted of the application of strict geographic cohorting of colonized infants and their nursing staff, the suspension of any new admission and a rigorous daily sterilization protocol for all surfaces and fomites in the ward. A posteriori characterization of the outbreak strain was performed using both traditional microbiology and molecular biology techniques, and whole genome sequencing, allowing to compare outbreak isolates with other strains collected in the previous two years. The results allowed to determine that the outbreak strain had been circulating inside the ward since the year before. Genomic characterization revealed that the strain carried a wide array of virulence and antibiotic resistance determinants, including gene blaTEM-206, which had never been reported in a clinical isolate of K. pneumoniae before. The presence of such a high number of determinants for antibiotic resistance imposes significant therapeutic limitations on the treatment of infections, thus, further epidemiological investigations are needed to evaluate the prevalence of the newly described variant.

Levels and effectiveness of oral retinol supplementation in VLBW preterm infants.

Retinol palmitate oral administration is convenient, but it is difficult to assess/monitor its nutritional status in preterm infants and literature is controversial about the administration route and the effectiveness of vitamin A supplementation. We primarily evaluated retinol plasma levels to assess the vitamin A nutritional status in preterm infants (<1500 g; 32 weeks) after 28 days of oral supplementation (3000 IU/kg/day, retinol palmitate drops), in addition to vitamin A standard amount as suggested by European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines. We then observed the rate of typical preterm pathologies in the supplemented group (31 newborns) and in 10 matching preterm infants, hospitalized in neonatal intensive care unit (NICU) in the same period, who received neither vitamin A supplementation nor parents allowed plasma sampling. Oral integration resulted in constant retinol plasma concentration around the desired level of 200 ng/mL, but without statistical increase during the study period. Due to the complexity of vitamin A metabolism and the immaturity of preterm infant's organs, retinol supplementation may had first saturated other needy tissues; therefore, plasmatic measures may not be consistent with improved global vitamin A body distribution. Therefore, achieving a constant retinol concentration is a valuable result and supportive for oral administration: decreasing levels, even after parenteral/enteral supplementation, were reported in the literature. In spite of favourable trend and no adverse events, we did not report statistical difference in co-morbidities. This investigation confirms the necessity to perform further trials in preterm newborns, to find an index reflecting the complex nutritional retinol status after oral administration of vitamin A, highlighting its effectiveness/tolerability in correlated preterm infant's pathologies.

Intersociety policy statement on the use of whole-exome sequencing in the critically ill newborn infant.

The rapid advancement of next-generation sequencing (NGS) technology and the decrease in costs for whole-exome sequencing (WES) and whole-genome sequening (WGS), has prompted its clinical application in several fields of medicine. Currently, there are no specific guidelines for the use of NGS in the field of neonatal medicine and in the diagnosis of genetic diseases in critically ill newborn infants. As a consequence, NGS may be underused with reduced diagnostic success rate, or overused, with increased costs for the healthcare system. Most genetic diseases may be already expressed during the neonatal age, but their identification may be complicated by nonspecific presentation, especially in the setting of critical clinical conditions. The differential diagnosis process in the neonatal intensive care unit (NICU) may be time-consuming, uncomfortable for the patient due to repeated sampling, and ineffective in reaching a molecular diagnosis during NICU stay. Serial gene sequencing (Sanger sequencing) may be successful only for conditions for which the clinical phenotype strongly suggests a diagnostic hypothesis and for genetically homogeneous diseases. Newborn screenings with Guthrie cards, which vary from country to country, are designed to only test for a few dozen genetic diseases out of the more than 6000 diseases for which a genetic characterization is available. The use of WES in selected cases in the NICU may overcome these issues. We present an intersociety document that aims to define the best indications for the use of WES in different clinical scenarios in the NICU. We propose that WES is used in the NICU for critically ill newborn infants when an early diagnosis is desirable to guide the clinical management during NICU stay, when a strong hypothesis cannot be formulated based on the clinical phenotype or the disease is genetically heterogeneous, and when specific non-genetic laboratory tests are not available. The use of WES may reduce the time for diagnosis in infants during NICU stay and may eventually result in cost-effectiveness.

Strategies for preventing group B streptococcal infections in newborns: a nation-wide survey of Italian policies.

BACKGROUND: There are no Italian data regarding the strategies for preventing neonatal group B streptococcal (GBS) infection. We conducted a national survey in order to explore obstetrical, neonatal and microbiological practices for the GBS prevention. METHODS: Three distinct questionnaires were sent to obstetricians, neonatologists and microbiologists. Questionnaires included data on prenatal GBS screening, maternal risk factors, intrapartum antibiotic prophylaxis, microbiological information concerning specimen processing and GBS antimicrobial susceptibility. RESULTS: All respondent obstetrical units used the culture-based screening approach to identify women who should receive intrapartum antibiotic prophylaxis, and more than half of the microbiological laboratories (58%) reported using specimen processing consistent with CDC guidelines. Most neonatal units (89 out of 107, 82%) reported using protocols for preventing GBS early-onset sepsis consistent with CDC guidelines. CONCLUSIONS: The screening-based strategy is largely prevalent in Italy, and most protocols for preventing GBS early-onset sepsis are consistent with CDC guidelines. However, we found discrepancies in practices among centers that may reflect the lack of Italian guidelines issued by public health organizations.

Mediterranean diet, folic acid, and neural tube defects.

The Mediterranean diet has been for a very long time the basis of food habits all over the countries of the Mediterranean basin, originally founded on rural models and low consumption of meat products and high-fat/high-processed foods. However, in the modern era, the traditional Mediterranean diet pattern is now progressively eroding due to the widespread dissemination of the Western-type economy, life-style, technology-driven culture, as well as the globalisation of food production, availability and consumption, with consequent homogenisation of food culture and behaviours. This transition process may affect many situations, including pregnancy and offspring's health. The problem of the diet during pregnancy and the proper intake of nutrients are nowadays a very current topic, arousing much debate. The Mediterranean dietary pattern, in particular, has been associated with the highest risk reduction of major congenital anomalies, like the heterogeneous class of neural tube defects (NTDs). NTDs constitute a major health burden (0.5-2/1000 pregnancies worldwide) and still remain a preventable cause of still birth, neonatal and infant death, or significant lifelong disabilities. Many studies support the finding that appropriate folate levels during pregnancy may confer protection against these diseases. In 1991 one randomised controlled trial (RCT) demonstrated for the first time that periconceptional supplementation of folic acid is able to prevent the recurrence of NTDs, finding confirmed by many other subsequent studies. Anyway, the high rate of unplanned/unintended pregnancies and births and other issues hindering the achievement of adequate folate levels in women in childbearing age, induced the US government and many other countries to institute mandatory food fortification with folic acid. The actual strategy adopted by European Countries (including Italy) suggests that women take 0,4 mg folic acid/die before conception. The main question is which intervention, between folic acid supplementation, foods fortification or both, linked to a healthy life-style and diet pattern may represent the best method in preventing NTDs. The aim of this review is to describe the actual situation in NTDs prevention, with a special attention to the Italiancontext concerning this delicate and controversial subject.

An Italian Prospective Experience on the Association Between Congenital Cytomegalovirus Infection and Autistic Spectrum Disorder.

The aim of this retrospective study, with prospective data collection, was to correlate congenital cytomegalovirus (CMV) infection with autism spectrum disorder (ASD) and to define its prevalence. Seventy proven congenitally-infected infants, born between 2007 and 2012, were referred to our centre for CMV diagnosis and follow-up, which consisted of a consolidated protocol allowing an early evaluation of autism. We considered four children 2-year old, two of whom, at the age of 3, were diagnosed with ASD demonstrating a 2-3 fold higher prevalence (2.86%), than that in general Italian population (0.66-1.36%).Our protocol enabled us to make the earliest diagnosis and highlight the role of the virus among other causes of autism, which may be a long term sequela of congenital CMV.

Neonatal Group B Streptococcal Disease in Otherwise Healthy Infants: Failure of Specific Neonatal Immune Responses.

Only a small proportion of newborn infants exposed to a pathogenic microorganism develop overt infection. Susceptibility to infection in preterm infants and infants with known comorbidities has a likely multifactorial origin and can be often attributed to the concurrence of iatrogenic factors, environmental determinants, underlying pathogenic processes, and probably genetic predisposition. Conversely, infection occurring in otherwise healthy full-term newborn infants is unexplained in most cases. Microbial virulence factors and the unique characteristics of the neonatal immune system only partially account for the interindividual variability in the neonatal immune responses to pathogens. We here suggest that neonatal infection occurring in otherwise healthy infants is caused by a failure of the specific protective immunity to the microorganism. To explain infection in term and preterm infants, we propose an extension of the previously proposed model of the genetic architecture of infectious diseases in humans. We then focus on group B streptococcus (GBS) disease, the best characterized neonatal infection, and outline the potential molecular mechanisms underlying the selective failure of the immune responses against GBS. In light of the recent discoveries of pathogen-specific primary immunodeficiencies and of the role of anticytokine autoantibodies in increasing susceptibility to specific infections, we hypothesize that GBS disease occurring in otherwise healthy infants could reflect an immunodeficiency caused either by rare genetic defects in the infant or by transmitted maternal neutralizing antibodies. These hypotheses are consistent with available epidemiological data, with clinical and epidemiological observations, and with the state of the art of neonatal physiology and disease. Studies should now be designed to comprehensively search for genetic or immunological factors involved in susceptibility to severe neonatal infections.

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts.

Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4- or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1ß. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1ß. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.