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.

Pharmacokinetic and Pharmacodynamic Considerations of Antibiotic Use in Neonates.

The selection of an appropriate dose of a given antibiotic for a neonate not only requires knowledge of the drug's basic pharmacokinetic (PK) and pharmacodynamic (PD) properties but also the profound effects that organ development might have on the volume of distribution and clearance, both of which may affect the PK/PD of a drug. Interest has grown in alternative antibiotic dosing strategies that are better aligned with the antibiotic's PK and PD properties. These strategies should be used in conjunction with minimum inhibitory concentration measurements and therapeutic drug monitoring to measure their potential success. They can also guide the clinician in tailoring the delivery of antibiotics to suit an individual patient's needs. Model-informed precision dosing, such as Bayesian forecasting dosing software (which incorporates PK/PD population models), may be utilized to optimize antibiotic exposure in neonatal populations. Consequently, optimizing the antibiotic dose and exposure in each newborn requires expertise in different fields. It drives the collaboration of physicians together with lab technicians and quantitative clinical pharmacologists.

Antibiotic prophylaxis for ophthalmia neonatorum in Italy: results from a national survey and the Italian intersociety new position statements.

BACKGROUND: Ophthalmia neonatorum is an acute conjunctivitis that occurs in newborns within the first month of life. The most serious infections are due to Chlamydia trachomatis and Neisseria gonorrhoeae, that may cause permanent damages. The use of ophthalmic prophylaxis varies widely around the world, according to the different health and socio-economic contexts. To date in Italy there is no a clear legislation regarding ophthalmia neonatorum prophylaxis at birth. METHODS: We invited all birth centers in Italy to carry out a retrospective survey relating the last three years. We collected data regarding demographics of neonates, drugs used for ophthalmic prophylaxis and results of the screening of pregnant women for Chlamydia trachomatis and Neisseria gonorrhoeae vaginal infections. RESULTS: Among 419 birth centers, 302 (72,1%) responded to the survey. Overall 1041384 neonates, 82,3% of those born in the three years considered, received ophthalmic prophylaxis. Only 4,585 (0,4%) of them received one of the drugs recommended by the WHO. The Centers that participated to the survey reported 12 episodes of Chlamydial conjunctivitis and no Gonococcal infection in the three years. Only 38% of the Centers performed vaginal swabs to pregnant women: 2,6% screened only for Neisseria, 9,6% only for Chlamydia and 25,8% for both germs. CONCLUSIONS: The data obtained from the survey showed a low incidence of neonatal conjunctivitis due to either Neisseria gonorrhoeae or Chlamydia trachomatis in Italy. Due to the lack of legislation regulating the prophylaxis of ophthalmia neonatorum in newborns, the Italian Society of Neonatology, the Italian Society of Obstetrics and Gynecology and the Italian Society of Perinatal Medicine have recently issued new recommendations on this topic.

Decreased incidence of late-onset sepsis during the SARS-CoV-2 pandemic in Italy: a multicentric study on a cohort of infants requiring major surgery.

Changes in the organization of the clinical care wards, requested by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, have influenced the environmental circulation of other pathogens. The implementation of prevention procedures may have led to a decrease in the incidence of healthcare-associated infections. We aimed to investigate the impact of prevention and control measures for preventing the COVID-19 spread on the incidence of bacterial sepsis and invasive fungal infections in neonates and infants requiring major surgery. We compared the incidence of bacterial and fungal sepsis and their risk factors observed before the SARS-CoV-2 pandemic (from 01/10/2018 to 29/02/2020) with those observed during the pandemic (from 01/03/2020 to 07/05/2021) in 13 level III Neonatal Intensive Care Units in Italy, through a secondary analysis of data, collected during a prospective multicenter study (REF). The patients enrolled were infants within three months of life, hospitalized in the two periods in the participating centers to undergo major surgery. Among 541 enrolled patients, 324 (59.9%) were born in the pre-pandemic period and 217 (40.1%) during the pandemic. The incidence density (ID) of any infection in the pre-pandemic period was 16.0/1000 patient days versus 13.6/1000 patient days in the pandemic period (p < 0.001). One hundred and forty-five (145/324; 44.8%) patients developed at least one episode of bacterial sepsis in the pre-pandemic period, versus 103/217 (31.8%) patients, during the pandemic (p = 0.539). Concerning fungal sepsis, 12 (3.7%) patients had one episode in the pre-pandemic period versus 11 (5.1%) patients during the pandemic (p = 0.516). The most significant differences observed in the use of healthcare procedures were the reduction of CVC days, the reduced use of antibiotics pre-surgery, and that of proton pump inhibitors during the SARS-CoV-2 pandemic compared with the previous period. CONCLUSIONS: In our cohort of patients with major surgical needs, the reduction of CVC days, pre-surgery antibiotics administration, and current use of proton pump inhibitors, during the SARS-CoV-2 pandemic, led to a decrease in the incidence of late-onset sepsis. WHAT IS KNOWN: • Most cases of late-onset sepsis in neonates are referred to as central line-associated bloodstream infections. • In adults, the COVID-19 outbreak negatively influenced healthcare-associated infection rates and infection clusters within hospitals. WHAT IS NEW: • In neonates and infants undergoing major surgery the incidence density of infections was lower in the pandemic period than before. • The most significant differences observed in the use of healthcare procedures were the reduction of CVC days, the reduced use of antibiotics before surgery, and that of proton pump inhibitors during the pandemic compared with previously.

Lumbar Puncture and Meningitis in Infants with Proven Early- or Late-Onset Sepsis: An Italian Prospective Multicenter Observational Study.

Background: To evaluate the rates of lumbar puncture (LP) in infants with culture-proven sepsis. Study design: We prospectively enrolled 400 infants with early- or late-onset sepsis due to Group B streptococcus (GBS) or Eschericha coli, diagnosed within 90 days of life. Rates of LP and potential variables associated with LP performance were evaluated. Moreover, cerebrospinal fluid (CSF) characteristics and results of the molecular analysis were investigated. Results: LP was performed in 228/400 (57.0%) infants; 123/228 LPs (53.9%) were performed after antibiotic initiation, hampering the ability to identify the pathogen in the CSF culture. However, polymerase chain reaction increased the probability of positive results of CSF analysis compared to microbiological culture (28/79, 35.4% vs. 14/79, 17.7%, p = 0.001). Severe clinical presentation and GBS infection were associated with higher LP rates. The rate of meningitis was 28.5% (65/228). Conclusions: Rates of LP are low in culture-proven neonatal sepsis and antibiotics are frequently given before LP is carried out. Thus meningitis may be underestimated, and the chances of giving an effective therapy to the newborn are reduced. LP should be performed before the start of antibiotics when there is a clinical suspicion of infection.

Immunization technologies: Time to consider new preventative solutions for respiratory syncytial virus infections.

New technologies for the prevention of infectious diseases are emerging to address unmet medical needs, in particular, the use of long-acting monoclonal antibodies (mAb) to prevent Respiratory Syncytial Virus (RSV) lower respiratory tract disease in infants during their first RSV season. The lack of precedent for mAbs for broad population protection creates challenges in the assessment of upcoming prophylactic long-acting mAbs for RSV, with associated consequences in legislative and registration categorization, as well as in recommendation, funding, and implementation pathways. We suggest that the legislative and regulatory categorization of preventative solutions should be decided by the effect of the product in terms of its impact on the population and health-care systems rather than by the technology used or its mechanism of action. Immunization can be passive and active, both having the same objective of prevention of infectious diseases. Long-acting prophylactic mAbs work as passive immunization, as such, their recommendations for use should fall under the remit of National Immunization Technical Advisory Groups or other relevant recommending bodies for inclusion into National Immunization Programs. Current regulations, policy, and legislative frameworks need to evolve to embrace such innovative preventative technologies and acknowledge them as one of key immunization and public health tools.

Timing of Symptoms of Early-Onset Sepsis after Intrapartum Antibiotic Prophylaxis: Can It Inform the Neonatal Management?

The effectiveness of "inadequate" intrapartum antibiotic prophylaxis (IAP administered < 4 h prior to delivery) in preventing early-onset sepsis (EOS) is debated. Italian prospective surveillance cohort data (2003-2022) were used to study the type and duration of IAP according to the timing of symptoms onset of group B streptococcus (GBS) and E. coli culture-confirmed EOS cases. IAP was defined "active" when the pathogen yielded in cultures was susceptible. We identified 263 EOS cases (GBS = 191; E. coli = 72). Among GBS EOS, 25% had received IAP (always active when beta-lactams were administered). Most IAP-exposed neonates with GBS were symptomatic at birth (67%) or remained asymptomatic (25%), regardless of IAP duration. Among E. coli EOS, 60% were IAP-exposed. However, IAP was active in only 8% of cases, and these newborns remained asymptomatic or presented with symptoms prior to 6 h of life. In contrast, most newborns exposed to an "inactive" IAP (52%) developed symptoms from 1 to >48 h of life. The key element to define IAP "adequate" seems the pathogen's antimicrobial susceptibility rather than its duration. Newborns exposed to an active antimicrobial (as frequently occurs with GBS infections), who remain asymptomatic in the first 6 h of life, are likely uninfected. Because E. coli isolates are often unsusceptible to beta-lactam antibiotics, IAP-exposed neonates frequently develop symptoms of EOS after birth, up to 48 h of life and beyond.

Intersociety Position Statement on the Prevention of Ophthalmia Neonatorum in Italy.

There is currently no worldwide agreement on the real need to administer conjunctival antibiotics to neonates at birth to prevent neonatal conjunctivitis (usually defined as ophthalmia neonatorum) by Chlamydia trachomatis and Neisseria gonorrhoeae. Therefore, there is wide variability in antibiotic administration, conditioned mainly by the social and health context. In Italy, a law enacted in 1940 required doctors and midwives to administer ophthalmic prophylaxis with 2% silver nitrate to all newborns at birth. This law was repealed in 1975 and since then there has been no clear guidance on the use of ophthalmia neonatorum prophylaxis at birth. Since neonatal conjunctivitis caused by C. trachomatis and N. gonorrhoeae is not reported, we carried out a nationwide survey of 1,041,384 neonates across all Italian birth centers to evaluate the incidence of ophthalmia neonatorum and the current practice of prophylaxis. After analyzing the results, we formulated an intersociety position statement on the prevention of ophthalmia neonatorum to update and standardize this prevention strategy in Italy.

SCN2A and arrhythmia: A potential correlation? A case report and literature review.

Variants in SCN2A, encoding the voltage-gated sodium channel Nav1.2, are commonly associated with developmental and epileptic encephalopathy. Although animal studies demonstrated a role for Nav1.2 in intraventricular conduction, heart anomalies have been only occasionally described in patients with SCN2A variants. In this report we trace the prenatal and neonatal history of a fetus/newborn with a de novo pathogenic variant in the SCN2A gene identified by prenatal trio whole-exome sequencing (WES). In addition to more typically SCN2A-associated neurological manifestations, the patient showed sustained tachyarrhythmia, potentially expanding the phenotypic spectrum associated with SCN2A variants and raising the question of whether cardiological assessment and prompt pharmacological intervention in SCN2A channelopathies to avoid heart complications might be beneficial. To the best of our knowledge, this represents the first clinical description of a SCN2A phenotype in a prenatal setting, as well as the first SCN2A diagnosis achieved by prenatal trio-WES approach.

Real-World Studies of Respiratory Syncytial Virus Hospitalizations among Moderate/Late Preterm Infants Exposed to Passive Immunoprophylaxis with Palivizumab.

This article aims to assess the real-world effectiveness of palivizumab immunoprophylaxis against respiratory syncytial virus (RSV)-associated hospitalization (RSVH) rates in otherwise healthy moderate/late preterm infants and discuss the role of palivizumab in preventing acute and long-term outcomes. We identified studies in the PubMed and Embase databases that reported patient-level data on (1) exposure to palivizumab in preterm infants born between 29 and 35 weeks of gestational age (or subsets within this range) ≤ 2 years of chronological age, and (2) the outcome of RSVH. Six studies assessed RSVH in infants this gestational age who had been exposed or not to palivizumab and reported patient-level data. Exposure was associated with a reduction in RSVH rates that was comparable to the reduction seen in controlled clinical trials (weighed mean 4.0-fold reduction). RSV immunoprophylaxis in preterm infants within 29 to 35 weeks of gestational age is associated with a considerably lower burden of RSVH. KEY POINTS: · RSV is the leading cause of lower respiratory tract infection hospitalization in infants.. · Palivizumab prevents RSVH in a real-world scenario.. · Immunoprophylaxis should be used in high-risk infants..

Congenital Toxoplasmosis: The State of the Art.

Infection with the protozoan parasite Toxoplasma gondii occurs worldwide and usually causes no symptoms. However, a primary infection of pregnant women, may infect the fetus by transplacental transmission. The risk of mother-to-child transmission depends on week of pregnancy at the time of maternal infection: it is low in the first trimester, may reach 90% in the last days of pregnancy. Inversely, however, fetal disease is more severe when infection occurs early in pregnancy than later. Systematic serologic testing in pregnant women who have no antibodies at the beginning of pregnancy, can accurately reveal active maternal infection. Therefore, the risk of fetal infection should be assessed and preventive treatment with spiramycin must be introduced as soon as possible to reduce the risk of mother-to-child transmission, and the severity of fetal infection. When maternal infection is confirmed, prenatal diagnosis with Polymerase Chain Reaction (PCR) on amniotic fluid is recommended. If fetal infection is certain, the maternal treatment is changed to a combination of pyrimethamine-sulfonamide and folinic acid. Congenitally infected newborns are usually asymptomatic at birth, but at risk for tardive sequelae, such as blindness. When congenital infection is evident, disease include retinochoroiditis, cerebral calcifications, hydrocephalus, neurocognitive impairment. The diagnosis of congenital infection must be confirmed at birth and management, specific therapy, and follow-up with multidisciplinary counseling, must be guaranteed.

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.

Clinical Correlates of Placental Pathologic Features in Early-Onset Fetal Growth Restriction.

INTRODUCTION: The purpose of this study was to evaluate the association between placental pathologic features of maternal (MVM) or fetal (FVM) vascular malperfusion and clinical characteristics, sonographic findings and neonatal outcome in a cohort of pregnancies complicated by early-onset (diagnosed before 32 weeks of gestational age) fetal growth restriction (FGR). METHODS: A prospective cohort study included 250 singleton early-onset FGR pregnancies diagnosed, followed up and delivered at a single center. Placental pathologic lesions were classified according to standard recommendations. Logistic regression and Cox analysis were used to evaluate outcomes adjusting for confounders. RESULTS: Overall features of severe placental MVM and FVM were observed in 29.6% (74/250) and 12.8% (32/250) of the subjects, respectively. Severe placental MVM lesions were more common among subjects with umbilical artery Doppler Pulsatility Index >95th than ≤95th percentile (50/120 as opposed to 24/130, Adj odds ratio [OR] = 3, 95% CI = 1.6-5.4) and Cerebroplacental ratio <5th than ≥5th percentile (48/115 as opposed to 26/135, Adj OR = 2.7, 95% CI = 1.5-4.9). Mean time from FGR diagnosis to delivery was shorter among subjects with severe MVM (25.5 days, 95% CI = 20.6-30.2, Adj. OR = 1.9, 95% CI = 1.9, 95% CI = 1.4-2.5) when compared to both those with mild/moderate MVM (36.5 days [95% CI = 27.2-45, p = 0.04]) or no MVM (39.4, 95% CI = 35.4-43.4, p < 0.001). Finally, severe FVM was associated with an increased risk of perinatal/neonatal death or severe brain lesions (9/28 in subjects with perinatal/neonatal death/brain lesions as compared to 23/222 in controls, Adj OR = 3, 95% CI = 1.05-8.6) or severe adverse neonatal outcomes (13/46 in subjects with severe adverse outcome as compared to 19/204 among controls, Adj OR = 3.2, 95% CI = 1.2-8.5). CONCLUSIONS: In early-onset FGR, placental pathologic features of MVM and FVM are, in different regards, associated to severity of clinical picture, abnormal Doppler markers of placental and fetal circulation and of neonatal outcome, respectively.

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.

Hypertrophic cardiomyopathy in infant newborns of diabetic mother: a heterogeneous condition, the importance of anamnesis, physical examination and follow-up.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) in neonates is a rare and heterogeneous disorder. HCM accounts for 25 to 40% of all pediatric cardiomyopathy cases and the highest incidence in pediatric population is reported in children < 1 year. CASE PRESENTATION: we report two clinical cases of neonates, born to mothers respectively with a pre-pregnancy insulin-dependent diabetic mellitus type 2 and a suspected diabetes, with inadequate prenatal glycemic control for the first and underestimated glycemic control for the second case, with a different evolution. In the first case, a slow evidence of improvement of the HCM was observed, persuading us to the diagnosis of a diabetes-related HCM; In the second case the progressive worsening of the HCM during follow-up in association with further investigations, resulted in the diagnosis of Pompe disease. CONCLUSIONS: Hypertrophic cardiomyopathy in newborns can be the clinical expression of different underlying disorders. We aim to show the importance both to reassess maternal and family history and critically evaluate the physical examination in order to address the correct differential diagnosis. Furthermore it is important to continue a regular cardiologic follow-up for this pathology with neonatal onset to prevent a poor prognosis.

Neonatal SARS-CoV-2 Infection: Practical Tips.

The recent viral pandemic in Wuhan, Hubei, China has led to the identification of a new species of beta-coronavirus, able to infect humans, the 2019-nCoV, later named SARS-CoV-2. SARS-CoV-2 causes a clinical syndrome named COVID-19, which presents with a spectrum of symptoms ranging from mild upper respiratory tract infection to severe pneumonia, with acute respiratory distress syndrome and frequent death. All age groups are susceptible to the infection, but children, especially infants, seem to be partially spared, having a more favorable clinical course than other age groups. There is currently no clear evidence showing vertical transmission and intrauterine SARS-CoV-2 infection in fetuses of women developing COVID-19 pneumonia in late pregnancy, and even if transmission is possible, the SARS-CoV2 positivity of the mother does not require delivery by caesarean section, does not contraindicate the management of the infant in rooming-in and allows breastfeeding. This review provides an overview on the biology of the virus, on the pathogenesis of the infection, with particular attention to pregnancy and neonatal age, on the clinical presentation of infection in newborns and young infants and summarizes the international recommendations currently available on the clinical care of neonates with SARS-CoV2 infection or at risk of catching the virus. The main objective of the review is to provide an update especially focused to the clinical management of COVID-19 infection in the perinatal and neonatal age.

Invasive Candida Infections in Neonates after Major Surgery: Current Evidence and New Directions.

Infections represent a serious health problem in neonates. Invasive Candida infections (ICIs) are still a leading cause of mortality and morbidity in neonatal intensive care units (NICUs). Infants hospitalized in NICUs are at high risk of ICIs, because of several risk factors: broad spectrum antibiotic treatments, central catheters and other invasive devices, fungal colonization, and impaired immune responses. In this review we summarize 19 published studies which provide the prevalence of previous surgery in neonates with invasive Candida infections. We also provide an overview of risk factors for ICIs after major surgery, fungal colonization, and innate defense mechanisms against fungi, as well as the roles of different Candida spp., the epidemiology and costs of ICIs, diagnosis of ICIs, and antifungal prophylaxis and treatment.

A global point prevalence survey of antimicrobial use in neonatal intensive care units: The no-more-antibiotics and resistance (NO-MAS-R) study.

BACKGROUND: Global assessment of antimicrobial agents prescribed to infants in the neonatal intensive care unit (NICU) may inform antimicrobial stewardship efforts. METHODS: We conducted a one-day global point prevalence study of all antimicrobials provided to NICU infants. Demographic, clinical, and microbiologic data were obtained including NICU level, census, birth weight, gestational/chronologic age, diagnoses, antimicrobial therapy (reason for use; length of therapy), antimicrobial stewardship program (ASP), and 30-day in-hospital mortality. FINDINGS: On July 1, 2019, 26% of infants (580/2,265; range, 0-100%; median gestational age, 33 weeks; median birth weight, 1800 g) in 84 NICUs (51, high-income; 33, low-to-middle income) from 29 countries (14, high-income; 15, low-to-middle income) in five continents received ≥1 antimicrobial agent (92%, antibacterial; 19%, antifungal; 4%, antiviral). The most common reasons for antibiotic therapy were "rule-out" sepsis (32%) and "culture-negative" sepsis (16%) with ampicillin (40%), gentamicin (35%), amikacin (19%), vancomycin (15%), and meropenem (9%) used most frequently. For definitive treatment of presumed/confirmed infection, vancomycin (26%), amikacin (20%), and meropenem (16%) were the most prescribed agents. Length of therapy for culture-positive and "culture-negative" infections was 12 days (median; IQR, 8-14) and 7 days (median; IQR, 5-10), respectively. Mortality was 6% (42%, infection-related). An NICU ASP was associated with lower rate of antibiotic utilization (p = 0·02). INTERPRETATION: Global NICU antibiotic use was frequent and prolonged regardless of culture results. NICU-specific ASPs were associated with lower antibiotic utilization rates, suggesting the need for their implementation worldwide. FUNDING: Merck & Co.; The Ohio State University College of Medicine Barnes Medical Student Research Scholarship.

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.