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.

Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

Anti-Inflammatory and Anti-Allergic Properties of Colostrum from Mothers of Full-Term and Preterm Babies: The Importance of Maternal Lactation in the First Days.

Our narrative review focuses on colostrum components, particularly those that influence the neonatal immune system of newborns. Colostrum is secreted in small volumes by the alveolar cells of the breast during the first two to five days after birth. Colostrum is poor in fat and carbohydrates, with larger protein and bioactive compounds than mature milk. It plays a crucial role in driving neonates' immunity, transferring those immunological factors which help the correct development of the neonatal immune system and support establishing a healthy gut microbiome. The newborn has an innate and adaptive immune system deficiency, with a consequent increase in infection susceptibility. In particular, neonates born prematurely have reduced immunological competencies due to an earlier break in the maternal trans-placenta transfer of bioactive components, such as maternal IgG antibodies. Moreover, during pregnancy, starting from the second trimester, maternal immune cells are conveyed to the fetus and persist in small quantities post-natal, whereby this transfer is known as microchimerism (MMc). Thus, preterm newborns are deficient in this maternal heritage, and have their own immune system under-developed, but colostrum can compensate for the lack. Early breastfeeding, which should be strongly encouraged in mothers of preterm and full-term babies, provides those immunomodulant compounds that can act as a support, allowing the newborn to face immune needs, including fronting infections and establishing tolerance. Moreover, making mothers aware that administering colostrum helps their infants in building a healthy immune system is beneficial to sustain them in the difficult post-partum period.

Fulminant echovirus 11 hepatitis in male non-identical twins in northern Italy, April 2023.

Echovirus 11 (E11) has recently been associated with a series of nine neonatal cases of severe hepatitis in France. Here, we present severe hepatitis caused by E11 in a pair of twins. In one of the neonates, the clinical picture evolved to fulminant hepatitis. The E11 genome showed 99% nucleotide identity with E11 strains reported in the cases in France. Rapid genome characterisation using next generation sequencing is essential to identify new and more pathogenetic variants.

Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in ∼40% of patients.

Mosquito-borne West Nile virus (WNV) infection is benign in most individuals but can cause encephalitis in <1% of infected individuals. We show that ∼35% of patients hospitalized for WNV disease (WNVD) in six independent cohorts from the EU and USA carry auto-Abs neutralizing IFN-α and/or -ω. The prevalence of these antibodies is highest in patients with encephalitis (∼40%), and that in individuals with silent WNV infection is as low as that in the general population. The odds ratios for WNVD in individuals with these auto-Abs relative to those without them in the general population range from 19.0 (95% CI 15.0-24.0, P value <10-15) for auto-Abs neutralizing only 100 pg/ml IFN-α and/or IFN-ω to 127.4 (CI 87.1-186.4, P value <10-15) for auto-Abs neutralizing both IFN-α and IFN-ω at a concentration of 10 ng/ml. These antibodies block the protective effect of IFN-α in Vero cells infected with WNV in vitro. Auto-Abs neutralizing IFN-α and/or IFN-ω underlie ∼40% of cases of WNV encephalitis.

LIMIT: LIfestyle and Microbiome InTeraction Early Adiposity Rebound in Children, a Study Protocol.

Childhood obesity is a strong predictor of adult obesity with health and economic consequences for individuals and society. Adiposity rebound (AR) is a rise in the Body Mass Index occurring between 3 and 7 years. Early adiposity rebound (EAR) occurs at a median age of 2 years and predisposes to a later onset of obesity. Since obesity has been associated with intestinal dysbiosis, we hypothesize that EAR could be related to early microbiome changes due to maternal/lifestyle changes and environmental exposures, which can increase the unhealthy consequences of childhood obesity. LIMIT is a prospective cohort study that aims at identifying the longitudinal interplay between infant gut microbiome, infant/maternal lifestyle, and environmental variables, in children with EAR vs. AR. Methods. The study evaluated 272 mother-infant pairs, enrolled at an Italian neonatal unit, at different time points (T0, at delivery; T1, 1 month; T2, 6 months; T3, 12 months; T4, 24 months; T5, 36 months after birth). The variables that were collected include maternal/infant anthropometric measurements, lifestyle habits, maternal environmental endocrine disruptor exposure, as well as infant AR. The LIMIT results will provide the basis for early identification of those maternal and infant modifiable factors on which to act for an effective and personalized prevention of childhood obesity.

Impact of SARS-CoV-2 infection during pregnancy and persistence of antibody response.

BACKGROUND: Pregnant women may be at an increased risk of developing severe or critical disease associated with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection causing severities during pregnancy. We performed a prospective study to describe the impact of SARS-CoV-2 infection on pregnancy outcomes and on the newborn, depending on the severity of the disease. The antibody response and persistence of SARS-CoV-2 anti-Spike (S) IgG, IgA and anti-Nu- cleocapsid (NCP) IgG, was investigated. METHODS: A total of 48 pregnant women with SARS-CoV-2 infection were enrolled, and sequential serum samples from 30 of them were collected until one year after infection. Outcomes of pregnan- cy and newborn parameters were evaluated in comparison with 200 uninfected controls. RESULTS: Asymptomatic infection was observed in 31/48 women (64.5%), mild COVID-19 in 12/48 women (25.0%), while 5/48 women (10.5%) developed pneumonia. Women with pneumonia mount- ed significantly higher levels of anti-S IgG, IgA and anti-NCP IgG between 1 and 3 months after onset of infection compared to asymptomatic women. Anti-S IgG persisted in the majority of women from 6 months to at least one year after infection, especially in those with symptomatic infection and pneumonia, while anti-S IgA and anti-NCP IgG declined earlier. Pregnancy complications and new- born parameters were not significantly different from those observed in uninfected controls. CONCLUSION: Anti-SARS-CoV-2 antibody development and persistence was not impaired in pregnant women, while SARS-CoV-2 infection did not cause major pregnancy or newborn complications in asymptomatic or symptomatic women, nor in women with pneumonia receiving prompt clinical care.

Leptin Levels of the Perinatal Period Shape Offspring's Weight Trajectories through the First Year of Age.

Background: Leptin is a hormone regulating lifetime energy homeostasis and metabolism and its concentration is important starting from prenatal life. We aimed to investigate the association of perinatal leptin concentrations with growth trajectories during the first year of life. Methods: Prospective, longitudinal study, measuring leptin concentration in maternal plasma before delivery, cord blood (CB), and mature breast milk and correlating their impact on neonate's bodyweight from birth to 1 year of age, in 16 full-term (FT), 16 preterm (PT), and 13 intrauterine growth-restricted (IUGR) neonates. Results: Maternal leptin concentrations were highest in the PT group, followed by IUGR and FT, with no statistical differences among groups (p = 0.213). CB leptin concentrations were significantly higher in FT compared with PT and IUGR neonates (PT vs. FT; IUGR vs. FT: p < 0.001). Maternal milk leptin concentrations were low, with no difference among groups. Maternal leptin and milk concentrations were negatively associated with all the neonates' weight changes (p = 0.017 and p = 0.006), while the association with CB leptin was not significant (p = 0.051). Considering each subgroup individually, statistical analysis confirmed the previous results in PT and IUGR infants, with the highest value in the PT subgroup. In addition, this group's results negatively correlated with CB leptin (p = 0.026) and showed the largest % weight increase. Conclusions: Leptin might play a role in neonatal growth trajectories, characterized by an inverse correlation with maternal plasma and milk. PT infants showed the highest correlation with hormone levels, regardless of source, seeming the most affected group by leptin guidance. Low leptin levels appeared to contribute to critical neonates' ability to recover a correct body weight at 1 year. An eventual non-physiological "catch-up growth" should be monitored, and leptin perinatal levels may be an indicative tool. Further investigations are needed to strengthen the results.

Identifying high-confidence variants in human cytomegalovirus genomes sequenced from clinical samples.

Understanding the intrahost evolution of viral populations has implications in pathogenesis, diagnosis, and treatment and has recently made impressive advances from developments in high-throughput sequencing. However, the underlying analyses are very sensitive to sources of bias, error, and artefact in the data, and it is important that these are addressed adequately if robust conclusions are to be drawn. The key factors include (1) determining the number of viral strains present in the sample analysed; (2) monitoring the extent to which the data represent these strains and assessing the quality of these data; (3) dealing with the effects of cross-contamination; and (4) ensuring that the results are reproducible. We investigated these factors by generating sequence datasets, including biological and technical replicates, directly from clinical samples obtained from a small cohort of patients who had been infected congenitally with the herpesvirus human cytomegalovirus, with the aim of developing a strategy for identifying high-confidence intrahost variants. We found that such variants were few in number and typically present in low proportions and concluded that human cytomegalovirus exhibits a very low level of intrahost variability. In addition to clarifying the situation regarding human cytomegalovirus, our strategy has wider applicability to understanding the intrahost variability of other viruses.

The dynamical interplay of perinatal leptin with birthweight and 3-month weight, in full-term, preterm, IUGR mother-infant dyads.

OBJECTIVE: To evaluate the dynamical interplay between perinatal leptin concentrations and neonatal weight evolution until 3 months of age. METHODS: In a prospective observational study, maternal, cord blood and neonatal plasma leptin concentrations were correlated to birthweight and 3-month weight in 26 full-term, 20 preterm, and 17 intrauterine growth restriction (IUGR) mother-neonate couples. RESULTS: The median of maternal, cord blood, neonatal leptin concentrations were significantly different among the three groups (p = 0.010; <0.001; =0.041 correspondingly). In the respect of the full-term group, higher concentrations were reported in preterm and IUGR mothers and lower concentrations in cord blood and neonatal plasma. The post-hoc comparisons showed that maternal concentrations were significantly higher in the IUGR group (p = 0.005 vs full-term), cord blood concentrations resulted always significantly lower (preterm, IUGR vs full-term p < 0.001) and neonatal concentrations were significantly lower in the preterm group (p = 0.018 vs full-term). Neonatal birthweight and 3-month weight were always significantly different among groups (p < 0.001), even if preterm and IUGR still had lower weight than full-term, the percent increasing of weight between birth and 3-month demonstrated that preterm and IUGR infants have grown significantly faster, (preterm, IUGR vs full-term p < 0.001). The univariable analysis showed a maternal leptin association with offspring' birthweight (R = -38%, p = 0.006) and with 3-month weight (R = -43%, p = 0.002). Accounting for confounders, these associations lost significance. Cord blood leptin concentrations positively correlated with birthweight and with 3-month weight (both, p < 0.001). The latter correlation, when adjusting for birthweight became negative (R = -43% p < 0.001). CONCLUSION: Our results showed that maternal leptin levels lost their influence on neonatal weight when considering confounders. At 3-month, once birthweight adjusted, the percent increasing of weight was statistically larger in preterm and IUGR than the full-term group and the correlation between cord blood leptin and weight turned negative, from positive at birth. These data may be a clue for further investigation on the relationship between perinatal leptin concentrations and catch-up growth.

Literature Review and an Italian Hospital Experience about Post-Natal CMV Infection Acquired by Breast-Feeding in Very Low and/or Extremely Low Birth Weight Infants.

Breastfeeding is recommended for all neonates due to a known variety of beneficial effects, but infants can be infected by cell-associated bacteria and viruses from breast milk, such as cytomegalovirus (CMV). The majority of CMV-seropositive breastfeeding women have a viral, self-restricted reactivation, can shed the virus in the milk for about 12 weeks after delivery, and can transmit the infection to their offspring. Post-natal CMV-infected term infants are mainly asymptomatic, while very low birth weight (VLBW, <1500 g) and extremely low birth weight (ELBW, <1000 g) infants may present with severe disease, short-term sequelae ranging from abnormalities in laboratory indexes to sepsis-like syndrome, and long-term sequelae such as developmental problems. Thus, the use of thermally treated maternal milk for VLBW/ELBW infants may be indicated to prevent/reduce the risk of CMV transmission. Different techniques, with varying efficacy in eradicating CMV and maintaining the activity of biological compounds in milk are available: long/short pasteurization, freeze-thawing, the use of microwaves, and ultraviolet-C irradiation. In our NICU, the use of maternal raw milk is always strongly recommended for term/preterm infants, but to reduce risk of CMV transmission, freeze-thawing mother's own milk is used in neonates with GA ≤ 30 weeks or/and weight ≤ 1000 g, usually regardless of serological maternal condition, as CMV screening is not routinely offered to pregnant women and the milk of seroimmune mothers is not evaluated for CMV reactivation, as its rate is similar to seroprevalence. Over the last 4 years, we had 10 VLBW/ELBW newborns in our NICU with late-onset sepsis and negative cultures. In these cases, the research of CMV DNA in neonatal urine or saliva, for the diagnosis of post-natal symptomatic infection (once congenital transmission has been excluded) may be useful and not invasive. The take-home message we would like to share is that acquired CMV infection should be considered in VLBW/ELBW infants breastfed by seropositive mothers and presenting severe symptoms-particularly sepsis with negative cultures. This could allow pediatricians to make better-quality diagnoses, perform supportive therapy, provide antiviral treatment if needed, or establish a "pre-emptive" therapy for these high-risk neonates.

Oral melatonin as a new tool for neuroprotection in preterm newborns: study protocol for a randomized controlled trial.

BACKGROUND: Prevention of neurodevelopmental impairment due to preterm birth is a major health challenge. Despite advanced obstetric and neonatal care, to date there are few neuroprotective molecules available. Melatonin has been shown to have anti-oxidant/anti-inflammatory effects and to reduce brain damage, mainly after hypoxic ischemic encephalopathy. The planned study will be the first aiming to evaluate the capacity of melatonin to mitigate brain impairment due to premature birth. METHOD: In our planned prospective, multicenter, double-blind, randomized vs placebo study, we will recruit, within 96 h of birth, 60 preterm newborns with a gestational age ≤ 29 weeks + 6 days; these infants will be randomly allocated to oral melatonin, 3 mg/kg/day, or placebo for 15 days. After the administration period, we will measure plasma levels of malondialdehyde, a lipid peroxidation product considered an early biological marker of melatonin treatment efficacy (primary outcome). At term-equivalent age, we will evaluate neurological status (through cerebral ultrasound, cerebral magnetic resonance imaging, vision and hearing evaluations, clinical neurological assessment, and screening for retinopathy of prematurity) as well as the incidence of bronchodysplasia and sepsis. We will also monitor neurodevelopmental outcome during the first 24 months of corrected age (using the modified Fagan Test of Infant Intelligence at 4-6 months and standardized neurological and developmental assessments at 24 months). DISCUSSION: Preterm birth survivors often present long-term neurodevelopmental sequelae, such as motor, learning, social-behavioral, and communication problems. We aim to assess the role of melatonin as a neuroprotectant during the first weeks of extrauterine life, when preterm infants are unable to produce it spontaneously. This approach is based on the supposition that its anti-oxidant mechanism could be useful in preventing neurodevelopmental impairment. Considering the short- and long-term morbidities related to preterm birth, and the financial and social costs of the care of preterm infants, both at birth and over time, we suggest that melatonin administration could lead to considerable saving of resources. This would be the first study addressing the role of melatonin in very low birth weight preterm newborns, and it could provide a basis for further studies on melatonin as a neuroprotection strategy in this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04235673 . Prospectively registered on 22 January 2020.

Onset of valganciclovir resistance in two infants with congenital cytomegalovirus infection.

Ganciclovir and its prodrug valganciclovir are elective treatments for cCMV. Neonates with important symptoms undergo 6 months of therapy to ameliorate/prevent symptoms and late sequelae, but evidence of resistance is emerging. Over the last 5 years, we took care of 59 cCMV infants and experienced two cases of resistance among nine cCMV infants receiving long-term valganciclovir therapy. In the first case, valganciclovir therapy was prolonged beyond 6 months due to severity of symptoms, control of viral load, and absence of adverse events. Resistance was detected in the 8th month of therapy. In the second case, after a significant reduction following valganciclovir administration and no adverse events, CMV viral load suddenly increased in the 6th month of therapy due to resistance. Both events were associated with UL97 gene mutation. The cCMV infants, affected by severe symptoms, remained in a steady state during treatment, and their later neurological development was coherent with initial seriousness of diagnosis. Prolonged therapeutic exposure may therefore be a risk for resistance, suggesting that constant dosage/weight adjustments, monthly surveillance of viral load, and therapeutic drug monitoring could be proposed to monitor resistance onset and optimize the therapy regime. The risk-benefit ratio for long-term therapy, including the possibility of resistance onset, alongside SNHL and neurodevelopmental improvement, should also be evaluated.

Oral vitamin A supplementation for ROP prevention in VLBW preterm infants.

Vitamin A administration may decrease any stage of retinopathy of prematurity (ROP) in preterm infants. To evaluate whether vitamin A oral supplementation could be preventive in ROP incidence and severity in VLBW infants, we compared results from 31 preterm infants, (< 1500 g or < 32 weeks) who, during a previous investigation, prospectively received 3000 UI/kg/die oral retinol palmitate drops, for 28 days, with 31 matching preterm newborns hospitalized in our NICU the same period, as control group. Although ROP incidence was similar, in the supplemented group, we had 9 cases of ROP grade 1, no ROP grade ≥ 2, in the un-supplemented group, 4 cases of ROP grade 1 and 6 ROP grade ≥ 2 (p = 0.018). The percentage of babies requiring treatment for ROP was 0 in treated and 16.6 in the un-treated group (p = 0.020). Moreover, Vitamin A administration showed a protective effect with an 88% risk reduction of developing severe ROP. Since vitamin A parenteral/IM administration presents some awareness, the results of this investigation may be important to plan further trials to confirm the usefulness of oral administration in mitigating the ROP severity of VLBW infants.ClinicalTrials.gov NCT02102711; may 03/06/2014.

Rapid detection of bacteria in bloodstream infections using a molecular method: a pilot study with a neonatal diagnostic kit.

Neonatal sepsis is a life-threatening condition and its early diagnosis is crucial for infant survival. Identifying responsible pathogens is a key step. Blood culture (BC) is the gold standard, but more rapid and specific diagnostic methods are needed. We evaluated the reliability and utility of 3 h turnaround time diagnostic molecular kit, "EuSepScreen lattanti "CE IVD marked, (EuSepScreen lattanti, Eurospital Spa Trieste, Italy) specifically targeted to detect 4 pathogens in neonatal sepsis: Klebsiella pneumoniae (KP), Escherichia coli (EC), Streptococcus agalactiae (GBS), and Lysteria monocytogenes. We evaluated 69 neonates, 40 full term and 29 preterm infants, with suspected bloodstream infection, who, overall the routine clinical procedures, were tested using the molecular kit. Kit results were compared to BC outcomes. Nineteen cases for early onset sepsis (EOS) were evaluated, 2 of them resulted positive to a molecular kit and to BC (both for GBS and EC). In the 50 cases of suspected late onset sepsis (LOS), 7 infants reported positive and coincident results to both the methods, in 3 further cases the molecular kit identified pathogens (EC) in neonates with negative BC result; in 10 cases BC revealed etiological pathogens exceeding the molecular kit possibility of identification. In case of EOS, results of the molecular kit were coincident to these of BC, but available in 3 h turnaround time, which is an advantage, so the kit may actually be an "add-on tool" for EOS, with reference to EC and GBS, but a larger study with a greater number of EOS cases are needed to validate its usefulness in the NICU. Regarding LOS the restricted panel of identifiable microorganisms failed to provide timely information for sepsis diagnosis, highlighting the need of enlarged number microorganisms for the diagnosis of LOS.Trial registration number: NCT03884894.

Neonatal HCMV-related polymicrogyria in seroimmune women: What is the optimal pregnancy management?

BACKGROUND: Human cytomegalovirus (HCMV) infection is the most common congenital infection in developed countries. Recent studies highlighted similar percentages of symptoms in HCMV congenitally-infected infants following either primary or non-primary maternal infections. OBJECTIVES: To highlight correlation between neonatal brain abnormalities, detected by ultrasounds and magnetic resonance image in HCMV congenitally-infected infants, and maternal virological parameters during pregnancy, especially in seroimmune mothers. STUDY DESIGN: We considered the 36 HCMV congenitally-infected infants (26 asymptomatic and 10 symptomatic) referred to our center over 4 consecutive years. Maternal serologic data during pregnancy were available for all cases. Neonatal cranial ultrasound and magnetic resonance images were related to maternal virological findings during pregnancy. RESULTS: Polymicrogyria was observed in 6/10 (60.0%) symptomatic and 0/26 (0%) asymptomatic newborns (p < 0.001). The 6 infants with polymicrogyria were all born to mothers who were HCMV IgG reactive with negative specific IgM, in the first trimester of pregnancy (range: 8-14 weeks). For these six women, pre-conceptional HCMV serologic information were absent and they all were considered immune for HCMV during pregnancy, therefore no further serologic investigation or specific educational and hygienic information were recommended during gestation. CONCLUSION: These data highlight the elevated frequency of polymicrogyria in HCMV congenitally-infected infants born to mothers defined as seroimmune in the early stage of pregnancy and having no pre-existing serologic information. The paper stresses the potential utility of pre-conceptional screening to define maternal infection reliably (primary vs non-primary), and allow evidence-based counseling in women with positive serology, suggesting also preventive hygienic measures during pregnancy.

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.

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.