Healthy preterm newborns: Altered innate immunity and impaired monocyte function.

Birth prior to 37 completed weeks of gestation is referred to as preterm (PT). Premature newborns are at increased risk of developing infections as neonatal immunity is a developing structure. Monocytes, which are key players after birth, activate inflammasomes. Investigations into the identification of innate immune profiles in premature compared to full-term infants are limited. Our research includes the investigation of monocytes and NK cells, gene expression, and plasma cytokine levels to investigate any potential differences among a cohort of 68 healthy PT and full-term infants. According to high-dimensional flow cytometry, PT infants have higher proportions of CD56+/- CD16+ NK cells and immature monocytes, and lower proportions of classical monocytes. Gene expression revealed lower proportions of inflammasome activation after in vitro monocyte stimulation and the quantification of plasma cytokine levels expressed higher concentrations of alarmin S100A8. Our findings suggest that PT newborns have altered innate immunity and monocyte functional impairment, and pro-inflammatory plasmatic profile. This may explain PT infants' increased susceptibility to infectious disease and should pave the way for novel therapeutic strategies and clinical interventions.

Cranial ultrasound in preterm infants ≤ 32 weeks gestation-novel insights from the use of very high-frequency (18-5 MHz) transducers: a case series.

The quality of cranial ultrasound has improved over time, with advancing technology leading to higher resolution, faster image processing, digital display, and back-up. However, some brain lesions may remain difficult to characterize: since higher frequencies result in greater spatial resolution, the use of additional transducers may overcome some of these limitations. The very high-frequency transducers (18-5 MHz) are currently employed for small parts and lung ultrasound. Here we report the first case series comparing the very high-frequency probes (18-5 MHz) with standard micro-convex probes (8-5 MHz) for cranial ultrasound in preterm infants. In this case series, we compared cranial ultrasound images obtained with a micro-convex transducer (8-5 MHz) and those obtained with a very high-frequency (18-5 MHz) linear array transducer in 13 preterm infants ≤ 32 weeks gestation (9 with cerebral abnormalities and 4 with normal findings). Ultrasound examinations using the very high-frequency linear transducer and the standard medium-frequency micro-convex transducer were performed simultaneously. We also compared ultrasound findings with brain MRI images obtained at term corrected age. Ultrasound images obtained with the very high-frequency (18-5 MHz) transducer showed high quality and accuracy. Notably, despite their higher frequency and expected limited penetration capacity, brain size is small enough in preterm infants, so that brain structures are close to the transducer, allowing for complete evaluation.    Conclusion: We propose the routine use of very high-frequency linear probes as a complementary scanning modality for cranial ultrasound in preterm infants ≤ 32 weeks gestation. What is Known: • Brain lesions in preterm infants may remain insufficiently defined through conventional cranial ultrasound scan. • Higher frequency probes  offer better spatial resolution but have a narrower filed of exploration and limited penetration capacity. What is New: • Very high-frequency probes were compared with standard medium-frequency probes for cranial ultrasound in infants  ≤ 32 weeks' gestation. • Thanks to the smaller skull size of preterm infants, the new very high-frequency transducers allowed a complete and accurate evaluation.

Serial clinical observation for management of newborns at risk of early-onset sepsis.

PURPOSE OF REVIEW: Current management approaches for asymptomatic neonates at risk of early onset sepsis remain controversial. Strategies based entirely on clinical observation (SCO, serial clinical observation) have gained consensus. RECENT FINDINGS: We briefly compare different strategies for managing asymptomatic newborns suggested in four high-income countries. Then this review details the existing differences in carrying out the SCO in the United Kingdom, the USA, and Italy; the experiences from the studies performed using the SCO; and open questions regarding this strategy. Advantages and limitations of SCO are also discussed. There is a need to assess which symptoms at birth are more predictive of early onset sepsis and therefore require immediate interventions versus those symptoms that can be monitored and re-evaluated. SUMMARY: SCO strategy may require changes in the processes of newborn care at birthing centers. Nonetheless, SCO is safe and is associated with fewer laboratory evaluations and unnecessary antibiotics. Thoughtful and thorough practices related to the care of all newborns will benefit any birthing centre. VIDEO ABSTRACT: http://links.lww.com/MOP/A40.

Worse global intellectual and worse neuropsychological functioning in preterm-born children at preschool age: a meta-analysis.

AIM: Preterm births (<32 weeks of gestational age) are associated with cognitive problems that are difficult to diagnose in infancy but potentially detectable at preschool age. This review aimed to evaluate the extent to which total intelligence quotient (IQ) and neuropsychological functions at ages three to five years differ between children born at <32 weeks gestational age or < 1500 g birth weight and children born at term. The secondary aim was to determine whether cognitive performance differs between extremely preterm (EPT)/extremely low birth weight (ELBW) children and very preterm (VPT) or very low birth weight (VLBW) children. METHODS: PubMed and PsycINFO databases were searched for cohort studies comparing IQ and neuropsychological functions in term-born and preterm-born children born after 1994. RESULTS: At ages three to five years, preterm-born children, compared with term-born ones, had worse IQ mean score (d = -0.77 [95% confidence interval -0.88 to -0.66]), attention, memory, visuomotor integration skill and executive functions. No differences were found between VPT/VLBW and EPT/ELBW children. CONCLUSION: Preterm-born children showed poorer IQ and neuropsychological functions compared with term-born subjects already at preschool age. The extent of differences is similar to that detected at a later age.

Effects of nutritional intake on disease severity in children with sickle cell disease.

BACKGROUND: Children with Sickle Cell Disease (SCD) may show growth failure in comparison to healthy peers. Many factors as hematological status, endocrine and/or metabolic dysfunction, and nutritional status, may play an important role in growth failure. The aim of this study was to assess whether impaired growth and nutritional intake can affect SCD severity during childhood. METHODS: We conducted an observational study on children with SCD referring to our clinic for routine follow-up visits in a 6-month period. We collected information on weight, height and body mass index (BMI) and calculated their respective standardized scores (z). The nutritional intake was assessed through the last 24-h recall intake of total calories, macro- (proteins, lipids, carbohydrates) and micronutrients (calcium, iron, phosphorus, vitamins B1, PP, A, C, B2). Disease severity was assessed through total hemoglobin (Hb) and fetal hemoglobin (HbF), and lactic dehydrogenase (LDH) levels, and through the total number and days of hospitalizations, as well as the lifetime episodes of acute chest syndrome (ACS). RESULTS: Twenty nine children (14 males, 15 females) with SCD were enrolled; their mean age was 9.95 years (SD 3.50, min 3.72, max 17.18). Z-weight and z-BMI were significantly directly related to total Hb. Food intake resulted significantly unbalanced in terms of total calorie intake, macro- and micronutrients, especially calcium, iron, vitamin B1 and C. Low intake of calcium and vitamin B1 were significantly inversely correlated with number and days of hospitalizations per year. Protein, lipid, phosphorus, and vitamin PP intakes resulted adequate but were inversely correlated with number and days of hospitalizations. Carbohydrate, lipid, iron, phosphorus, vitamins B1 and B2 intakes were significantly inversely correlated to HbF levels. CONCLUSIONS: This study showed that, in our population, inadequate nutritional intake, weight and BMI have a significant impact on SCD severity indices.

Ultrasound-Guided Centrally Inserted Central Catheter (CICC) Placement in Newborns: A Safe Clinical Training Program in a Neonatal Intensive Care Unit.

BACKGROUND: Centrally inserted central catheters (CICCs) are increasingly used in neonatal care. CICCs have garnered attention and adoption owing to their advantageous features. Therefore, achieving clinical competence in ultrasound-guided CICC insertion in term and preterm infants is of paramount importance for neonatologists. A safe clinical training program should include theoretical teaching and clinical practice, simulation and supervised CICC insertions. METHODS: We planned a training program for neonatologists for ultrasound-guided CICCs placement at our level III neonatal intensive care unit (NICU) in Modena, Italy. In this single-centre prospective observational study, we present the preliminary results of a 12-month training period. Two paediatric anaesthesiologists participated as trainers, and a multidisciplinary team was established for continuing education, consisting of neonatologists, nurses, and anaesthesiologists. We detail the features of our training program and present the modalities of CICC placement in newborns. RESULTS: The success rate of procedures was 100%. In 80.5% of cases, the insertion was obtained at the first ultrasound-guided venipuncture. No procedure-related complications occurred in neonates (median gestational age 36 weeks, IQR 26-40; median birth weight 1200 g, IQR 622-2930). Three of the six neonatologists (50%) who participated in the clinical training program have achieved good clinical competence. One of them has acquired the necessary skills to in turn supervise other colleagues. CONCLUSIONS: Our ongoing clinical training program was safe and effective. Conducting the program within the NICU contributes to the implementation of medical and nursing skills of the entire staff.

Fetal hepatic calcification in severe KAT6A (Arboleda-Tham) syndrome.

Arboleda-Tham syndrome (ARTHS, MIM 616268) is a rare genetic disease, due to a pathogenic variant of Lysine (K) Acetyltransferase 6A (KAT6A) with autosomal dominant inheritance. Firstly described in 2015, ARTHS is one of the more common causes of undiagnosed syndromic intellectual disability. Due to extreme phenotypic variability, ARTHS clinical diagnosis is challenging, mostly at early stage of the disease. Moreover, because of the wide and unspecific spectrum of ARTHS, identification of the syndrome during prenatal life rarely occurs. Therefore, reported cases of KAT6A syndrome have been identified primarily through clinical or research exome sequencing in a gene-centric approach. In order to expands the genotypic and phenotypic spectrum of ARTHS, we describe prenatal and postnatal findings in a patient with a novel frameshift KAT6A pathogenic variant, displaying a severe phenotype with previously unreported clinical features.

Neurodevelopmental outcome of neonatal seizures: A longitudinal study.

INTRODUCTION: Neonatal seizures (NS) are the most common neurological emergency in the neonatal period. The International League Against Epilepsy (ILAE) proposed a new classification of NS based on semiology and highlighted the correlation between semiology and aetiology. However, neurodevelopmental outcomes have not been comprehensively evaluated based on this new classification. AIMS: To evaluate neurodevelopmental outcomes and potential risk factors for severe outcomes in NS. METHODS: Patients with video electroencephalogram confirmed NS were evaluated. Seizure aetiology, cerebral magnetic resonance imaging (MRI) data, background electroencephalograms data, general movements, and neurodevelopmental outcomes were analysed. Severe outcomes were one of the following: death, cerebral palsy, Griffiths developmental quotient <70, epilepsy, deafness, or blindness. RESULTS: A total of 74 neonates were evaluated: 62 (83.8 %) with acute provoked NS (primarily hypoxic-ischaemic encephalopathy), and 12 (16.2 %) with neonatal-onset epilepsies (self-limited neonatal epilepsy, developmental and epileptic encephalopathy, cerebral malformations). Of these, 32 (43.2 %) had electrographic seizures, while 42 (56.7 %) had electroclinical seizures - 38 (90.5 %) were motor (42.1 % clonic) and 4 (9.5 %) were non-motor phenomena. Severe outcomes occurred in 33 of the 74 (44.6 %) participants. In multivariate analysis, neonatal-onset epilepsies (odds ratio [OR]: 1.3; 95 % confidence interval [CI]: 1.1-1.6), status epilepticus (OR: 5.4; 95 % CI: 1.5-19.9), and abnormal general movements (OR: 3.4; 95 % CI: 1.9-7.6) were associated with severe outcomes. CONCLUSIONS: At present, hypoxic-ischaemic encephalopathy remains the most frequent aetiology of NS. The prognosis of neonatal-onset epilepsies was worse than that of acute provoked NS, and status epilepticus was the most predictive factor for adverse outcomes.

Neurodevelopmental Outcome after Culture-Proven or So-Called Culture-Negative Sepsis in Preterm Infants.

(1) Background: Prematurity is a serious condition associated with long-term neurological disability. This study aimed to compare the neurodevelopmental outcomes of preterm neonates with or without sepsis. (2) Methods: This single-center retrospective case-control study included infants with birth weight < 1500 g and/or gestational age ≤ 30 weeks. Short-term outcomes, brain MRI findings, and severe functional disability (SFD) at age 24 months were compared between infants with culture-proven or culture-negative sepsis or without sepsis. A chi-squared test or Mann-Whitney U test was used to compare the clinical and instrumental characteristics and the outcomes between cases and controls. (3) Results: Infants with sepsis (all sepsis n = 76; of which culture-proven n = 33 and culture-negative n = 43) were matched with infants without sepsis (n = 76). Compared with infants without sepsis, both all sepsis and culture-proven sepsis were associated with SFD. In multivariate logistic regression analysis, SFD was associated with intraventricular hemorrhage (OR 4.7, CI 1.7-13.1, p = 0.002) and all sepsis (OR 3.68, CI 1.2-11.2, p = 0.021). (4) Conclusions: All sepsis and culture-proven sepsis were associated with SFD. Compared with infants without sepsis, culture-negative sepsis was not associated with an increased risk of SFD. Given the association between poor outcomes and culture-proven sepsis, its prevention in the neonatal intensive care unit is a priority.

Sustaining the Continued Effectiveness of an Antimicrobial Stewardship Program in Preterm Infants.

BACKGROUND: There are wide variations in antibiotic use in neonatal intensive care units (NICUs). Limited data are available on antimicrobial stewardship (AS) programs and long-term maintenance of AS interventions in preterm very-low-birth-weight (VLBW) infants. METHODS: We extended a single-centre observational study carried out in an Italian NICU. Three periods were compared: I. "baseline" (2011-2012), II. "intervention" (2016-2017), and III. "maintenance" (2020-2021). Intensive training of medical and nursing staff on AS occurred between periods I and II. AS protocols and algorithms were maintained and implemented between periods II and III. RESULTS: There were 111, 119, and 100 VLBW infants in periods I, II, and III, respectively. In the "intervention period", there was a reduction in antibiotic use, reported as days of antibiotic therapy per 1000 patient days (215 vs. 302, p < 0.01). In the "maintenance period", the number of culture-proven sepsis increased. Nevertheless, antibiotic exposure of uninfected VLBW infants was lower, while no sepsis-related deaths occurred. Our restriction was mostly directed at shortening antibiotic regimens with a policy of 48 h rule-out sepsis (median days of early empiric antibiotics: 6 vs. 3 vs. 2 in periods I, II, and III, respectively, p < 0.001). Moreover, antibiotics administered for so-called culture-negative sepsis were reduced (22% vs. 11% vs. 6%, p = 0.002), especially in infants with a birth weight between 1000 and 1499 g. CONCLUSIONS: AS is feasible in preterm VLBW infants, and antibiotic use can be safely reduced. AS interventions, namely, the shortening of antibiotic courses in uninfected infants, can be sustained over time with periodic clinical audits and daily discussion of antimicrobial therapies among staff members.

Early Skin-to-Skin Contact in Preterm Infants: Is It Safe? An Italian Experience.

BACKGROUND: Skin-to-skin contact (SSC) is one of the four components of kangaroo care (KC) and is also a valued alternative to incubators in low-income countries. SSC has also become a standard of care in high-income countries because of its short- and long-term benefits and its positive effect on infant growth and neurodevelopmental outcome. However, barriers in the implementation of SSC, especially with preterm infants, are common in NICUs because parents and health care professionals can perceive it as potentially risky for the clinical stability of preterm infants. Previous studies have assessed safety before and during SSC by monitoring vital parameters during short-time intervals. AIMS: To demonstrate the safety of early SSC in preterm infants during at least 90 min intervals. DESIGN: Prospective observational monocentric study. METHODS: Preterm infants born between June 2018 and June 2020 with a gestational age of ≤33 weeks and a birth weight of <2000 g were monitored while performing an SSC session during the first three weeks of life. Infants with necrotizing enterocolitis, sepsis, and congenital malformations on mechanical ventilation or with more than five apneas in the hour before SSC were excluded. Continuous oxygen saturation (SaO2), heart rate (HR), and respiratory rate (RR) were registered during an SSC session and in the hour before. The minimum duration of an SSC session was 90 min. Information regarding postmenstrual age (PMA), body weight, respiratory support, presence of a central venous catheter and the onset of sepsis within 72 h after a session was collected. Two physicians, blinded to infant conditions and the period of analysis (before or during SSC), evaluated desaturation episodes (SaO2 < 85%, >15 s), bradycardia (HR < 100, >15 s) and apneas (pause in breathing > 20 s associated with desaturation and/or bradycardia). A Wilcoxon rank sum test was used for the statistical analysis. RESULTS: In total, 83 episodes of SSC were analyzed for a total of 38 infants. The mean gestational age at birth was 29 weeks (range 23-33 weeks). Median PMA, days of life, and body weight at SSC were 31 weeks (range 25-34 weeks), 10 days (range 1-20 days), and 1131 g (range 631-2206 g), respectively. We found that 77% of infants were on respiratory support and 47% of them had a central venous catheter (umbilical or peripherally inserted central catheter) during SSC. The total duration of desaturation, bradycardia, and the number of apneas were not statistically different during the SSC session and the hour before. No catheter dislocation or ruptures were reported. CONCLUSIONS: These findings highlighted the safety of early SSC in preterm infants and the possibility of performing it in an intensive care setting in the first weeks of life. In addition, these findings should reassure health care professionals offering this practice as a standard of care. SSC plays a key role in the care of preterm infants due to its short- and long-term positive benefits, and it deserves to be increasingly offered to infants and their parents.

Late-Onset Sepsis Mortality among Preterm Infants: Beyond Time to First Antibiotics.

Objective: To investigate the impact of timing, in vitro activity and appropriateness of empirical antimicrobials on the outcome of late-onset sepsis among preterm very low birth weight infants that are at high risk of developing meningitis. Study design: This retrospective study included 83 LOS episodes in 73 very low birth weight infants born at ≤32 weeks' gestation with positive blood and/or cerebrospinal fluid culture or polymerase chain reaction at >72 h of age. To define the appropriateness of empirical antimicrobials we considered both their in vitro activity and their ideal delivery through the blood-brain barrier when meningitis was confirmed or not ruled out through a lumbar puncture. The primary outcome was sepsis-related mortality. The secondary outcome was the development of brain lesions. Timing, in vitro activity and appropriateness of empirical antimicrobials, were compared between fatal and non-fatal episodes. Uni- and multi-variable analyses were carried out for the primary outcome. Results: Time to antibiotics and in vitro activity of empirical antimicrobials were similar between fatal and non-fatal cases. By contrast, empirical antimicrobials were appropriate in a lower proportion of fatal episodes of late-onset sepsis (4/17, 24%) compared to non-fatal episodes (39/66, 59%). After adjusting for Gram-negative vs. Gram-positive pathogen and for other supportive measures (time to volume administration), inappropriate empirical antimicrobials remained associated with mortality (aOR, 10.3; 95% CI, 1.4-76.8, p = 0.023), while timing to first antibiotics was not (aOR 0.9; 95% CI, 0.7-1.2, p = 0.408; AUC = 0.88). The association between appropriate antimicrobials and brain sequelae was also significant (p = 0.024). Conclusions: The risk of sepsis-related mortality and brain sequelae in preterm very low birth weight infants is significantly associated with the appropriateness (rather than the timing and the in vitro activity) of empirical antimicrobials. Until meningitis is ruled out through lumbar puncture, septic very low birth weight infants at high risk of mortality should receive empiric antimicrobials with high delivery through the blood-brain barrier.

COVID-19 restrictions and hygiene measures reduce the rates of respiratory infections and wheezing among preterm infants.

BACKGROUND AND AIM: During the 2020 and 2021 Italian COVID-19 pandemic social restrictions and strict hygiene measures were recommended to limit the spread of SARS-CoV-2. We aimed to assess whether rates of respiratory infections and wheezing in preterm infants have changed during the pandemic. METHODS: Single center, retrospective study. Preterm infants in the first 6 months of life discharged home prior to (Period 1, January 2017 - December 2019) or during the pandemic (Period 2, January 2020 - March 2021) were compared. Rates of respiratory infection and wheezing in preterm infants with or without bronchopulmonary dysplasia (BDP) were assessed. RESULTS: During period 2 premature infants had lower rates of respiratory infections (36 out of 55 in Period 1 vs 11 out of 28 in Period 2, P=0.023) and wheezing (20 out of 55 in Period 1 vs 1 out of 28 in Period 2, P=0.001). This difference remained significant when infants with BPD (all grades) were analyzed separately (respiratory infections 26 out of 40 in Period 1 vs 7 out of 24 in Period 2, P=0.005; wheezing 16 out of 40 in Period 1 vs 1 out of 24 in Period 2, P=0.001). In contrast, respiratory infections and wheezing in preterm infants without BPD did not change after pandemic. CONCLUSIONS: Episodes of respiratory infections and wheezing among preterm infants were reduced during pandemic. We highlight the importance of proper family education for preventing respiratory tract infections in preterm infants with BPD, beyond the extraordinary conditions of the COVID-19 pandemic.

Therapeutic hypothermia is associated with changes in prognostic value of general movements.

BACKGROUND AND AIMS: General movements (GMs) have been recognized as the most accurate clinical tools for predicting cerebral palsy (CP). This study aimed to compare the type and prognostic value of abnormal GMs in infants with hypoxic ischemic encephalopathy treated or not with therapeutic hypothermia (TH). MATERIALS AND METHODS: This was a single-center retrospective study. We compared GMs of 55 cooled term infants versus 30 non-cooled term infants with hypoxic ischemic encephalopathy (HIE) and their motor outcome at 24 months of age. We also included data regarding early brain MRI scans. RESULTS: Rates of cerebral palsy was 5.4% and 46.7% in cooled and non-cooled infants respectively (p < 0.001). None of cooled infants showed cramped-synchronized GMs, whereas among non-cooled infants the cramped-synchronized pattern was present in 17.2% and 20% of infants at 1 and 3 months of age respectively. Hypokinesis was never seen in cooled infants and it was present in 23.3% of non-cooled ones. Absent fidgety correlated with CP in 14% and 73% of cooled and non-cooled infants respectively. At brain MRI cooled infants had fewer and less severe cerebral lesions compared to non-cooled infants (p = 0.003). CONCLUSIONS: Abnormal GMs are reduced in infants treated with TH. Hypokinesis and cramped-synchronized GMs are not observed in cooled infants and the associations between absent fidgety movements and CP it is largely abolished. TH is associated with changes in prognostic value of GMs.

Antimicrobial Resistance Pattern and Empirical Antibiotic Treatments in Neonatal Sepsis: A Retrospective, Single-Center, 12-Year Study.

Neonatal sepsis is an important cause of morbidity and mortality in neonatal intensive care units (NICUs). Continuous evaluation of antimicrobial resistance (AMR) profiles is advised to implement antimicrobial stewardship (AMS) programs and establish effective empiric antibiotic protocols. AMS may reduce AMR in NICUs and improve sepsis outcomes. In this retrospective observational study, we report data on culture-positive neonatal sepsis, assessing differences after the implementation of an AMS program (2011-2016 vs. 2017-2022). A total of 215 positive bacterial cultures from 169 infants were retrieved, with 79 early-onset (36.7%) and 136 late-onset (63.3%) sepsis episodes. Frequent causative agents for early-onset sepsis were S. agalactiae and E. coli, all susceptible to empiric treatment. Late-onset sepsis was mainly caused by Enterobacterales and S. aureus. Aminoglycosides, cefotaxime, and piperacillin-tazobactam resistance among Enterobacterales was substantially low; S. aureus was mostly susceptible to oxacillin and vancomycin. There were no differences in mortality and multidrug-resistant pathogens rates between the two study periods. There were five episodes of fungal late-onset sepsis, mostly due to C. albicans, of which one was fatal. The microbial distribution pattern and AMR profiles overlapped with other European studies. Because susceptibility patterns are rapidly changing worldwide, with the emerging threat of Methicillin-resistant S. aureus and extended-spectrum beta-lactamases producers, infection prevention and control practices and AMS strategies require continuous optimization to limit selection pressure and AMR escalation.

Neurodevelopmental Outcome and Neuroimaging of Very Low Birth Weight Infants from an Italian NICU Adopting the Family-Centered Care Model.

BACKGROUND: Improvements in perinatal care have substantially decreased mortality rates among preterm infants, yet their neurodevelopmental outcomes and quality of life persist as a pertinent public health concern. Family-centered care has emerged as a holistic philosophy that promotes effective alliances among patients, families, and healthcare providers to improve the quality of care. AIMS: This longitudinal prospective study aims to evaluate the neurodevelopmental outcomes and brain MRI findings in a cohort of preterm newborns admitted to a neonatal intensive care unit (NICU) adopting a family-centered care model. METHODS: Very low birth weight (VLBW) infants admitted to the NICU of Modena between 2015 and 2020 were enrolled. Infants who underwent conventional brain magnetic resonance imaging (MRI) at term-equivalent age were included. Neurodevelopmental follow-up was performed until the age of 24 months by a multidisciplinary team using the Amiel-Tison neurological assessment and the Griffiths Mental Developmental Scales (GMDS-R). Neurodevelopmental outcomes were classified as major sequelae (cerebral palsy, DQ ≤ 70, severe sensory impairment), minor sequelae (minor neurological signs such as clumsiness or DQ between 71 and 85), and normal outcomes (no neurological signs and DQ > 85). Risk factors for severe outcomes were assessed. RESULTS: In total, 49 of the 356 infants (13.8%) died before hospital discharge, and 2 were excluded because of congenital disorders. Of the remaining 305 infants, 222 (72.8%) completed the 24 month follow-up and were included in the study. Neurodevelopmental outcomes were classified as normal (n = 173, 77.9%), minor (n = 34, 15.3%), and major sequelae (n = 15, 6.8%). Among 221 infants undergoing brain MRI, 76 (34.4%) had major lesions (intraventricular hemorrhage, hemorrhagic parenchymal infarction, periventricular leukomalacia, and large cerebellar hemorrhage). In the multivariate regression model, the retinopathy of prematurity (OR 1.8; p value 0.016) and periventricular-intraventricular hemorrhage (OR 5.6; p value < 0.004) were associated with major sequelae. CONCLUSIONS: We reported low rates of severe neurodevelopmental outcomes in VLBW infants born in an Italian NICU with FCC. Identifying the risk factors for severe outcomes can assist in tailoring and optimizing early interventions on an individual basis, both within the NICU and after discharge.

Continuous Fentanyl Infusion in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia: Background, Aims, and Study Protocol for Time-Concentration Profiles.

Therapeutic hypothermia (TH) is the standard of care for newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE). Discomfort and pain during treatment are common and may affect the therapeutic efficacy of TH. Opioid sedation and analgesia (SA) are generally used in clinical practice, and fentanyl is one of the most frequently administered drugs. However, although fentanyl's pharmacokinetics (PKs) may be altered by hypothermic treatment, the PK behavior of this opioid drug in cooled newborns with HIE has been poorly investigated. The aim of this phase 1 study protocol (Trial ID: FentanylTH; EUDRACT number: 2020-000836-23) is to evaluate the fentanyl time-concentration profiles of full-term newborns with HIE who have been treated with TH. Newborns undergoing TH receive a standard fentanyl regimen (2 mcg/Kg of fentanyl as a loading dose, followed by a continuous infusion-1 mcg/kg/h-during the 72 h of TH and subsequent rewarming). Fentanyl plasma concentrations before bolus administration, at the end of the loading dose, and 24-48-72-96 h after infusion are measured. The median, maximum, and minimum plasma concentrations, together with drug clearance, are determined. This study will explore the fentanyl time-concentration profiles of cooled, full-term newborns with HIE, thereby helping to optimize the fentanyl SA dosing regimen during TH.

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.

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.