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Background: Prematurity is the strongest predictor of bronchopulmonary dysplasia (BPD). Most previous studies investigated additional risk factors by conventional statistics, while the few studies applying artificial intelligence, and specifically machine learning (ML), for this purpose were mainly targeted to the predictive ability of specific interventions. This study aimed to apply ML to identify, among routinely collected data, variables predictive of BPD, and to compare these variables with those identified through conventional statistics., Methods: Very preterm infants were recruited; antenatal, perinatal, and postnatal clinical data were collected. A BPD prediction model was built using conventional statistics, and nine supervised ML algorithms were applied for the same purpose: the results of the best-performing model were described and compared with those of conventional statistics., Results: Both conventional statistics and ML identified the degree of immaturity (low gestational age and/or birth weight), need for mechanical ventilation, and absent or reversed end diastolic flow (AREDF) in the umbilical arteries as risk factors for BPD. Each of the two approaches also identified additional potentially predictive clinical variables., Conclusion: ML algorithms might be useful to integrate conventional statistics in identifying novel risk factors, in addition to prematurity, for the development of BPD in very preterm infants. Specifically, the identification of AREDF status as an independent risk factor for BPD by both conventional statistics and ML highlights the opportunity to include detailed antenatal information in clinical predictive models for neonatal diseases., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background and Aim: Caffeine is routinely used for the prophylaxis of prematurity-related apnoeas. We aimed to evaluate the effect of caffeine maintenance on cardiovascular and cerebrovascular haemodynamics using a non-invasive multimodal monitoring in preterm infants during the transitional period., Methods: Infants <32 weeks' gestational age (GA) were enrolled in this observational prospective study. The following parameters were recorded before and after the administration of caffeine citrate 5 mg/kg using near-infrared spectroscopy, pulse oximetry and electrical velocimetry: heart rate, cardiac output, stroke volume, cardiac contractility, systemic vascular resistance (SVR), perfusion index, peripheral and cerebral oxygenation, cerebral fractional oxygen extraction, correlation index between cerebral oxygenation and heart rate (TOHRx, marker of cerebrovascular reactivity). Multilevel mixed-effects linear models were used to assess the impact of caffeine and of relevant clinical covariates on each parameter., Results: Seventy-seven infants (mean GA 29.3 ± 2.5 weeks, mean birthweight 1148 ± 353 g) were included. Caffeine administration was associated with increased SVR (B = 0.623, p = 0.004) and more negative TOHRx values (B = -0.036, p = 0.022), which suggest improved cerebrovascular reactivity., Conclusions: Caffeine administration at maintenance dosage during postnatal transition is associated with increased systemic vascular tone and improved cerebrovascular reactivity. A possible role for caffeine-mediated inhibition of adenosine receptors may be hypothesized., Impact: This study provides a thorough and comprehensive overview of multiple cerebrovascular and cardiovascular parameters, monitored non-invasively by combining near-infrared spectroscopy, electrical velocimetry and pulse oximetry, before and after the administration of caffeine at maintenance dosage in preterm infants during postnatal transition. Caffeine was associated with an improvement in cerebrovascular reactivity and with a slight but significant increase in systemic vascular resistance, with no additional effects on other cardiovascular and cerebrovascular parameters. Our results support the safety of caffeine treatment even during a phase at risk for haemodynamic instability such as postnatal transition and suggest potential beneficial effects on cerebral haemodynamics., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Studies on late talkers (LTs) highlighted their heterogeneity and the relevance of describing different communicative profiles., Aims: To examine lexical skills and gesture use in expressive (E-LTs) vs. receptive-expressive (R/E-LTs) LTs through a structured task., Methods and Procedures: Forty-six 30-month-old screened LTs were distinguished into E-LTs (n= 35) and R/E-LTs (n= 11) according to their receptive skills. Lexical skills and gesture use were assessed with a Picture Naming Game by coding answer accuracy (correct, incorrect, no response), modality of expression (spoken, spoken-gestural, gestural), type of gestures (deictic, representational), and spoken-gestural answers' semantic relationship (complementary, equivalent, supplementary)., Outcomes and Results: R/E-LTs showed lower scores than E-LTs for noun and predicate comprehension with fewer correct answers, and production with fewer correct and incorrect answers, and more no responses. R/E-LTs also exhibited lower scores in spoken answers, representational gestures, and equivalent spoken-gestural answers for noun production and in all spoken and gestural answers for predicate production., Conclusions and Implications: Findings highlighted more impaired receptive and expressive lexical skills and lower gesture use in R/E-LTs compared to E-LTs, underlying the relevance of assessing both lexical and gestural skills through a structured task, besides parental questionnaires and developmental scales, to describe LTs' communicative profiles., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Approximately half of very preterm infants with respiratory distress syndrome (RDS) fail treatment with nasal continuous positive airway pressure (NCPAP) and need mechanical ventilation (MV)., Objectives: Our aim with this study was to evaluate if nasal intermittent positive pressure ventilation (NIPPV) during less invasive surfactant treatment (LISA) can improve respiratory outcome compared with NCPAP., Materials and Methods: We carried out an open-label randomized controlled trial at tertiary neonatal intensive care units in which infants with RDS born at 25 +0 -31 +6 weeks of gestation between December 1, 2020 and October 31, 2022 were supported with NCPAP before and after surfactant administration and received NIPPV or NCPAP during LISA. The primary endpoint was the need for a second dose of surfactant or MV in the first 72 h of life. Other endpoints were need and duration of invasive and noninvasive respiratory supports, changes in SpO 2 /FiO 2 ratio after LISA, and adverse effect rate., Results: We enrolled 101 infants in the NIPPV group and 99 in the NCPAP group. The unadjusted odds ratio for the composite primary outcome was 0.873 (95% confidence interval: 0.456-1.671; p = .681). We found that the SpO 2 /FiO 2 ratio was transiently higher in the LISA plus NIPPV than in the LISA plus NCPAP group, while adverse effects of LISA had similar occurrence in the two arms., Conclusions: The application of NIPPV or NCPAP during LISA in very preterm infants supported with NCPAP before and after surfactant administration had similar effects on the short-term respiratory outcome and are both safe. Our study does not support the use of NIPPV during LISA., (© 2024 Wiley Periodicals LLC.)

Background: Premature birth is known to affect the newborn's autonomic nervous system (ANS) maturation, with potential short and long-term impact on their neurobehavioral development. The purpose of the study was to investigate the effects of maternal directed singing and speaking on the preterm infants' autonomic nervous system (ANS) maturation as measured by the heart rate variability (HRV) parameters., Methods: In this multi-center randomized clinical trial, 30 stable preterm infants (m = 29,6 weeks of gestational age), without any abnormalities were randomized into an intervention (16) or a control group (14). HRV was measured weekly, for a total of 80 recordings during hospitalization, as well as before and after each session of singing or speaking., Results: The intervention group showed a significant increase of the percentage value of HRV power in the high frequency range when compared to the control group (p = 0.044). More specifically, the maternal singing significantly increased the high frequency power and decreased the low/high frequency power ratio (p = 0.037)., Conclusions: The preterm infant's vagal activity significantly increased in the intervention group, potentially enhancing their ANS maturation. The effect is specifically evidenced in the singing condition., Impact: Maternal singing affects the autonomic nervous system maturation of preterm hospitalized newborns in the NICU. No previous studies investigated how early vocal parental intervention can affect preterm infants developement, throught their autonomic nervous system maturation. Early Vocal Contact as an early intervention involving parents has a positive impact on preterm infant's development and it can be easily implemented in the care of preterm infants., Trial Registration: NCT04759573, retrospectively registered, 17 February 2021., (© 2023. The Author(s).)

Background: The management of respiratory distress syndrome (RDS) in premature newborns is based on different types of non-invasive respiratory support and on surfactant replacement therapy (SRT) to avoid mechanical ventilation as it may eventually result in lung damage. European guidelines currently recommend SRT only when the fraction of inspired oxygen (FiO 2 ) exceeds 0.30. The literature describes that early SRT decreases the risk of bronchopulmonary dysplasia (BPD) and mortality. Lung ultrasound score (LUS) in preterm infants affected by RDS has proven to be able to predict the need for SRT and different single-center studies have shown that LUS may increase the proportion of infants that received early SRT. Therefore, the aim of this study is to determine if the use of LUS as a decision tool for SRT in preterm infants affected by RDS allows for the reduction of the incidence of BPD or death in the study group., Methods/design: In this study, 668 spontaneously-breathing preterm infants, born at 25 +0 to 29 +6  weeks' gestation, in nasal continuous positive airway pressure (nCPAP) will be randomized to receive SRT only when the FiO2 cut-off exceeds 0.3 (control group) or if the LUS score is higher than 8 or the FiO2 requirements exceed 0.3 (study group) (334 infants per arm). The primary outcome will be the difference in proportion of infants with BPD or death in the study group managed compared to the control group., Discussion: Based on previous published studies, it seems that LUS may decrease the time to administer surfactant therapy. It is known that early surfactant administration decreases BPD and mortality. Therefore, there is rationale for hypothesizing a reduction in BPD or death in the group of patients in which the decision to administer exogenous surfactant is based on lung ultrasound scores., Trial Registration: ClinicalTrials.gov identifier NCT05198375 . Registered on 20 January 2022., (© 2023. The Author(s).)

This study aims to assess the impact of time of onset and features of early foetal growth restriction (FGR) with absent end-diastolic flow (AEDF) on pregnancy outcomes and on preterm infants' clinical and neurodevelopmental outcomes up to 2 years corrected age. This is a retrospective, cohort study led at a level IV Obstetric and Neonatal Unit in Bologna, Italy. Pregnant women were eligible if having singleton pregnancies, with no major foetal anomaly detected, and diagnosed with early FGR + AEDF (defined as FGR + AEDF detected before 32 weeks gestation). Early FGR + AEDF was further classified according to time of onset and specific features into very early and persistent (VEP, FGR + AEDF first detected at 20-24 weeks gestation and persistent at the following scans), very early but transient (VET, FGR + AEDF detected at 20-24 weeks gestation and progressively improving at the following scans) and later (LA, FGR + AEDF detected between 25 and 32 weeks gestation). Pregnancy and neonatal outcomes and infant follow-up data were collected and compared among groups. Neurodevelopment was assessed using the revised Griffiths Mental Developmental Scales (GMDS-R) 0-2 years. A regression analysis was performed to identify early predictors of preterm infants' neurodevelopmental impairment. Fifty-two pregnant women with an antenatal diagnosis of early FGR + AEDF were included in the study (16 VEP, 14 VET, 22 LA). Four intrauterine foetal deaths occurred, all in the VEP group (p = 0.010). Compared to LA infants, VEP infants were born with lower gestational age and lower birth weight, had lower arterial cord blood pH and were at higher risk for intraventricular haemorrhage and periventricular leukomalacia (p < 0.05 for all comparisons). At 12 months, VEP infants had worse GMDS-R scores, both in the general quotient (mean [SD] 91.8 [12.4] vs 104.6 [8.7] in LA) and in the performance domain (mean [SD] 93.3 [15.4] vs 108.8 [8.8] in LA). This latter difference persisted at 24 months (mean [SD] 68.3 [17.0] vs 92.9 [17.7] in LA). In multivariate analysis, at 12 months corrected age, PVL was found to be an independent predictor of impaired general quotient, while the features and timing of antenatal Doppler alterations predicted worse scores in the performance domain.   Conclusion: Timing of onset and features of early FGR + AEDF might impact differently on neonatal clinical and neurodevelopmental outcomes. Shared awareness of the importance of FGR + AEDF features between obstetricians and neonatologists may offer valuable tools for antenatal counselling and for tailoring pregnancy management and neonatal follow-up in light of specific antenatal and neonatal risk factors. What is Known: • Foetal growth restriction (FGR), together with antenatal umbilical Doppler abnormalities, is known to affect maternal and neonatal outcomes. • Infants born preterm and growth-restricted face the highest risk for neurodevelopmental impairment, especially when FGR occurs early during pregnancy (early FGR, before 32 weeks gestation). What is New: • The timing of onset and features of FGR and antenatal umbilical Doppler abnormalities impact differently on maternal and neonatal outcomes; when FGR and Doppler abnormalities occur very early, at the limit of neonatal viability, and persist until delivery, infants face the highest risk for neurodevelopmental impairment. • Shared knowledge between obstetricians and neonatologists about timing of onset and features of FGR would provide a valuable tool for informed antenatal counselling in high-risk pregnancies., (© 2023. The Author(s).)

This prospective observational study aimed to evaluate whether lung fluids, assessed by lung ultrasonography and transthoracic electrical bioimpedance (TEB), may be influenced by the presence of a haemodynamically significant patent ductus arteriosus (hsPDA) in very preterm infants during the transitional period. Infants < 32 weeks of gestational age (GA) admitted to the neonatal intensive care units of IRCCS AOU Bologna and Niguarda Metropolitan Hospital of Milan (Italy) underwent a daily assessment of a lung ultrasound score (LUS) and of a TEB-derived index of thoracic fluid contents (TFC) during the first 72 h after birth. Echocardiographic scans were simultaneously performed to evaluate the concomitant ductal status (hsPDA vs. restrictive or closed duct). The correlation between LUS, TFC, and the ductal status was tested using generalized estimating equations. Forty-six infants (median GA: 29 [interquartile range, IQR: 27-31] weeks; median birth weight: 1099 [IQR: 880-1406] g) were included. At each daily evaluation, the presence of a hsPDA was associated with significantly higher LUS and TFC compared with a restrictive or closed ductus (p < 0.01 for all comparisons). These results were confirmed significant even after adjustment for GA and for the ongoing modality of respiratory support. Conclusion: Even during the first 72 h of life, the presence of a hsPDA determines a significant increase in pulmonary fluids which can be non-invasively detected and monitored over time using lung ultrasonography and TEB. What is Known: • Lung ultrasonography provides a non-invasive assessment of lung fluids and is widely used in neonatal settings. • In preterm infants, the persistence of a haemodynamically significant patent ductus arteriosus (hsPDA) over the first weeks can negatively affect pulmonary outcomes. What is New: • The presence of aan hsPDA is associated with increased lung fluids since early postnatal phases. • Lung ultrasonography and transthoracic electrical bioimpedance can effectively monitor lung fluid clearance in preterm infants with a hsPDA during the transitional period, with potential clinical implications., (© 2023. The Author(s).)

Infants born preterm are at a high risk of both gut microbiota (GM) dysbiosis and neurodevelopmental impairment. While the link between early dysbiosis and short-term clinical outcomes is well established, the relationship with long-term infant health has only recently gained interest. Notably, there is a significant overlap in the developmental windows of GM and the nervous system in early life. The connection between GM and neurodevelopment was first described in animal models, but over the last decade a growing body of research has also identified GM features as one of the potential mediators for human neurodevelopmental and neuropsychiatric disorders. In this narrative review, we provide an overview of the developing GM in early life and its prospective relationship with neurodevelopment, with a focus on preterm infants. Animal models have provided evidence for emerging pathways linking early-life GM with brain development. Furthermore, a relationship between both dynamic patterns and static features of the GM during preterm infants' early life and brain maturation, as well as neurodevelopmental outcomes in early childhood, was documented. Future human studies in larger cohorts, integrated with studies on animal models, may provide additional evidence and help to identify predictive biomarkers and potential therapeutic targets for healthy neurodevelopment in preterm infants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Beghetti, Barone, Brigidi, Sansavini, Corvaglia, Aceti and Turroni.)

Objective: To evaluate the relationship between impaired brain growth and structural brain abnormalities at term-equivalent age (TEA) and neurodevelopment in extremely-low-birthweight (ELBW) infants over the first 2 years., Methods: ELBW infants born from 2009 through 2018 and undergoing brain magnetic resonance imaging (MRI) at TEA were enrolled in this retrospective cohort study. MRI scans were reviewed using a validated quali-quantitative score, including several white and grey matter items. Neurodevelopment was assessed at 6, 12, 18, and 24 months using the Griffiths scales. The independent associations between MRI sub-scores and the trajectories of general and specific neurodevelopmental functions were analyzed by generalized estimating equations., Results: One-hundred-nine ELBW infants were included. White matter volume reduction and delayed myelination were associated with worse general development (b -2.33, p=0.040; b -6.88, p=0.049 respectively), social skills (b -3.13, p=0.019; b -4.79, p=0.049), and eye-hand coordination (b -3.48, p=0.009; b -7.21, p=0.045). Cystic white matter lesions were associated with poorer motor outcomes (b -4.99, p=0.027), while white matter signal abnormalities and corpus callosum thinning were associated with worse non-verbal cognitive performances (b -6.42, p=0.010; b -6.72, p=0.021 respectively). Deep grey matter volume reduction correlated with worse developmental trajectories., Conclusions: Distinctive MRI abnormalities correlate with specific later developmental skills. This finding may suggest that TEA brain MRI may assist with neurodevelopmental prediction, counselling of families, and development of targeted supportive interventions to improve neurodevelopment in ELBW neonates., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Late talkers represent a heterogeneous population. We aimed to describe communication profiles of low-risk preterm and full-term late talkers according to their receptive and expressive vocabulary size, considering communicative, linguistic, cognitive, and motor skills, as well as biological and environmental risk factors., Methods: Sixty-eight late talkers (33 born low-risk preterm and 35 full-term) were identified through a language screening at 30 months. Parents filled out the Italian Short Forms of the MacArthur Bates Communicative Development Inventories and the Socio Conversational Skills Rating Scales. Children were assessed with the Picture Naming Game test and the Bayley Scales of Infant and Toddler Development., Results: A two-step cluster analysis identified three distinct profiles among late talkers according to their receptive and expressive vocabulary size. Severe late talkers (25%) showed less frequent use of pointing, limited verbal imitation, receptive vocabulary size, lexical and sentence production, responsiveness and assertiveness, and lower cognitive scores than mild late talkers (40%). Moderate late talkers (35%) showed less frequent verbal imitation, limited lexical and sentence production and lower cognitive scores than mild late talkers. Male gender was significantly more represented in the severe late profile, whereas other biological and environmental factors did not differ among the three profiles., Conclusions: Findings highlighted the relevance of assessing communicative, lexical, grammar, pragmatic, and cognitive skills to describe late talkers' profiles. A deeper investigation of phonological skills might also contribute to a further understanding of interindividual variability in this population., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aims to evaluate whether the assessment of a lung ultrasound score (LUS) by lung ultrasonography and of thoracic fluid contents (TFC) by electrical cardiometry may predict RDS severity and the development of bronchopulmonary dysplasia (BPD) in preterm infants with respiratory distress (RDS). Infants ≤ 34 weeks' gestation admitted with RDS to two neonatal intensive care units were prospectively enrolled in this observational study. A simultaneous evaluation of LUS and TFC was performed during the first 72 h. The predictivity of LUS and TFC towards mechanical ventilation (MV) need after 24 h and BPD development was evaluated using receiver operating characteristic analysis. Sixty-four infants were included. The area under the curve (AUC) for the prediction of MV need was 0.851 (95%CI, 0.776-0.925, p < 0.001) for LUS and 0.793 (95%CI, 0.724-0.862, p < 0.001) for TFC, while an AUC of 0.876 (95%CI, 0.807-0.946, p < 0.001) was obtained for combined LUS and TFC evaluation. LUS and TFC AUC for BPD prediction were 0.769 (95%CI, 0.697-0.842, p < 0.001) and 0.836 (95%CI, 0.778-0.894, p < 0.001), respectively, whereas their combined assessment yielded an AUC of 0.867 (95%CI, 0.814-0.919, p < 0.001). LUS ≥ 11 and TFC ≥ 40 were identified as cut-off values for MV need prediction, whereas LUS ≥ 9 and TFC ≥ 41.4 best predicted BPD development.   Conclusion: A combined evaluation of LUS and TFC by lung ultrasonography and EC during the first 72 h may represent a useful predictive tool towards short- and medium-term pulmonary outcomes in preterm infants with RDS. What is Known: • Lung ultrasonography is largely used in neonatal intensive care and can contribute to RDS diagnosis in preterm infants. • Little is known on the diagnostic and predictive role of TFC, measured by transthoracic electrical bioimpedance, in neonatal RDS. What is New: • Combining lung ultrasonography and TFC evaluation during the first 72 h can improve the prediction of RDS severity and BPD development in preterm infants with RDS and may aid to establish tailored respiratory approaches to improve these outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite recent improvements in neonatal care, moderate to severe bronchopulmonary dysplasia (BPD) is still associated with high mortality and with an increased risk of developing pulmonary hypertension (PH). This scoping review provides an updated overview of echocardiographic and lung ultrasound biomarkers associated with BPD and PH, and the parameters that may prognosticate their development and severity, which could be clinically helpful to undertake preventive strategies. A literature search for published clinical studies was conducted in PubMed using MeSH terms, free-text words, and their combinations obtained through appropriate Boolean operators. It was found that the echocardiography biomarkers for BPD, and especially those assessing right ventricular function, are reflective of the high pulmonary vascular resistance and PH, indicating a strong interplay between heart and lung pathophysiology; however, early assessment (e.g., during the first 1-2 weeks of life) may not successfully predict later BPD development. Lung ultrasound indicating poor lung aeration at day 7 after birth has been reported to be highly predictive of later development of BPD at 36 weeks' postmenstrual age. Evidence of PH in BPD infants increases risk of mortality and long-term PH; hence, routine PH surveillance in all at risk preterm infants at 36 weeks, including an echocardiographic assessment, may provide useful information. Progress has been made in identifying the echocardiographic parameters on day 7 and 14 to predict later development of pulmonary hypertension. More studies on sonographic markers, and especially on echocardiographic parameters, are needed for the validation of the currently proposed parameters and the timing of assessment before recommendations can be made for the routine clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Martini, Corsini, Corvaglia, Suryawanshi, Chan and Singh.)

The detrimental effects of oxidative stress (OS) can start as early as after conception. A growing body of evidence has shown the pivotal role of OS in the development of several pathological conditions during the neonatal period, which have been therefore defined as OS-related neonatal diseases. Due to the physiological immaturity of their antioxidant defenses and to the enhanced antenatal and postnatal exposure to free radicals, preterm infants are particularly susceptible to oxidative damage, and several pathophysiological cascades involved in the development of prematurity-related complications are tightly related to OS. This narrative review aims to provide a detailed overview of the OS-related pathophysiological mechanisms that contribute to the main OS-related diseases during pregnancy and in the early postnatal period in the preterm population. Particularly, focus has been placed on pregnancy disorders typically associated with iatrogenic or spontaneous preterm birth, such as intrauterine growth restriction, pre-eclampsia, gestational diabetes, chorioamnionitis, and on specific postnatal complications for which the role of OS has been largely ascertained (e.g., respiratory distress, bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, necrotizing enterocolitis, neonatal sepsis). Knowledge of the underlying pathophysiological mechanisms may increase awareness on potential strategies aimed at preventing the development of these conditions or at reducing the ensuing clinical burden.

Supplementation of infant and follow-up formula with probiotics or synbiotics has become a common practice. In 2011 and 2017, the evidence regarding the impact of these interventions was analysed systematically. Recently new evidence was published. To evaluate through a systematic review with network meta-analysis the evidence on the impact of infant formula supplemented with probiotics or synbiotics for healthy infants and 36-month-old toddlers. RCTs published between 1999-2019 for infant formulas supplemented with probiotics alone or synbiotics in healthy infants and toddlers were identified. Data analysis included clinical (gastrointestinal symptoms, risk reduction of infectious diseases, use of antibiotics, weight/height gain and frequency of adverse events) and non-clinical outcomes (changes in faecal microbiota and immune parameters). A random effect model was used. Hedges' standard mean difference (SMD) and risk ratio (RR) were calculated. Rank analysis was performed to evaluate the superiority of each intervention. Twenty-six randomised controlled trials with 35 direct comparisons involving 1957 children receiving probiotic-supplemented formula and 1898 receiving control formula were reviewed. The mean duration of intervention was 5.6 ± 2.84 months. Certain strains demonstrated a reduction in episodes of colic, number of days with fever and use of antibiotics; however, there was considerable heterogeneity which reduced the level of certainty of effect. No significant effects were observed on weight, height or changes in faecal proportions of Bifidobacteria, Lactobacillus, Bacteroides or Clostridia . Although there is some evidence that may support a potential benefit of probiotic or synbiotic supplementation of infant formulas, variation in the quality of existing trials and the heterogeneity of the data preclude the establishment of robust recommendations.

Antenatal Doppler disturbances are associated with fetal hypoxia and may induce a brain-sparing vascular redistribution at the expense of splanchnic circulation, possibly predisposing to gut complications. We aimed to compare several gastrointestinal outcomes among very-low-birthweight (VLBW) preterm infants with different antenatal Doppler features. VLBW infants born between 2010-2022 were retrospectively included and stratified into the following clusters based on antenatal Doppler characteristics: normal Doppler (controls); absent or reversed end-diastolic flow in the umbilical artery (UA-AREDF) alone or also in the ductus venosus (UA+DV-AREDF); and abnormal Doppler with or without brain-sparing redistribution. The following outcomes were evaluated: time to reach full enteral feeds (FEF), feeding intolerance (FI), necrotizing enterocolitis (NEC), and spontaneous intestinal perforation (SIP). Overall, 570 infants were included. Infants born following UA+DV-AREDF had significantly higher FI, NEC, and SIP rates and achieved FEF later compared to controls. Increased FI prevalence and a longer time to FEF compared to controls were also observed among UA-AREDF infants and in the presence of brain-sparing redistribution, which also increased NEC rates. Antenatal Doppler abnormalities exacerbate the gastrointestinal risks of preterm infants. Detailed knowledge of Doppler features can aid in identifying those at highest risk of intestinal complications who may benefit from tailored enteral feeding management.

Introduction: Down syndrome (DS) is the most common chromosomal disorder and it is caused by trisomy of chromosome 21 (Hsa21). Subjects with DS show a large heterogeneity of phenotypes and the most constant clinical features present are typical facies and intellectual disability (ID). Several studies demonstrated that trisomy 21 causes an alteration in the metabolic profile, involving among all the one-carbon cycle., Methods: We performed enzyme-linked immunosorbent assays (ELISAs) to identify the concentration of 5 different intermediates of the one-carbon cycle in plasma samples obtained from a total of 164 subjects with DS compared to 54 euploid subjects. We investigated: tetrahydrofolate (THF; DS n = 108, control n = 41), 5-methyltetrahydrofolate (5-methyl-THF; DS n = 140, control n = 34), 5-formyltetrahydrofolate (5-formyl-THF; DS n = 80, control n = 21), S-adenosyl-homocysteine (SAH; DS n = 94, control n = 20) and S-adenosyl-methionine (SAM; DS n = 24, control n = 15)., Results: Results highlight specific alterations of THF with a median concentration ratio DS/control of 2:3, a decrease of a necessary molecule perfectly consistent with a chromosomal dosage effect. Moreover, SAM and SAH show a ratio DS/control of 1.82:1 and 3.6:1, respectively., Discussion: The relevance of these results for the biology of intelligence and its impairment in trisomy 21 is discussed, leading to the final proposal of 5-methyl-THF as the best candidate for a clinical trial aimed at restoring the dysregulation of one-carbon cycle in trisomy 21, possibly improving cognitive skills of subjects with DS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vione, Ramacieri, Zavaroni, Piano, La Rocca, Caracausi, Vitale, Piovesan, Gori, Pirazzoli, Strippoli, Cocchi, Corvaglia, Locatelli, Pelleri and Antonaros.)

Night sleep and parental bedtime practices have rarely been investigated in late talkers. This study aimed to explore: night sleep, parental bedtime practices, and their associations in late talkers as well as individual, socio-demographic, and socio-relational factors affecting them. Parents of 47 30-month-old late talkers, born low-risk preterm ( n = 24) or full-term ( n = 23), with an expressive vocabulary size ≤10th percentile measured by the MacArthur-Bates Communicative Development Inventory Words and Sentences, and normal cognitive abilities measured by the Bayley Scales, completed the Infant Sleep Questionnaire, the Parental Interactive Bedtime Behaviour Scale, and the Parenting Stress Index Short Form. Results showed slight settling difficulties, night wakings, and frequent co-sleeping in late talkers. Encouraging autonomy practices were frequently used by parents, rather than active physical comforting ones. Recurrent settling difficulties were reported by parents who often applied encouraging autonomy practices, whereas greater night waking problems and frequent co-sleeping were reported by parents who often left their child crying. Low-risk preterm birth and mother's parenting stress predicted total sleep difficulties and night wakings; first-born, high maternal education level and mother's parenting stress predicted settling difficulties; mother's parenting stress was the only predictor for co-sleeping and leaving to cry. These findings have relevant implications for improving late talkers' night sleep and their parents' bedtime practices.

This observational study aimed to investigate whether predischarge cerebral oxygenation (CrSO 2 ), monitored by near-infrared spectroscopy, correlates with later psychomotor outcome in very preterm infants. Infants <32 weeks' gestation or <1500 g without evidence of major brain lesions underwent a 3-h continuous CrSO 2 monitoring before hospital discharge. Psychomotor development was assessed at 6, 12, 18, and 24 months using the Griffiths Mental Developmental Scales. The developmental quotients (DQ) at each follow-up appointment were correlated with predischarge CrSO 2 . Significant correlations were adjusted for possible confounders. Sixty-three infants were enrolled. A significant correlation between CrSO 2 and DQ was observed at 6 months ca (p=0.010), but not at later psychomotor assessments. This correlation was confirmed significant (b=0.274, p=0.038) even after the adjustment for relevant covariates.   Conclusion: According to these preliminary findings, the association between predischarge CrSO 2 and psychomotor development over the first 24 months in preterm infants without major brain lesions is time-limited. Hence, this parameter may not represent an effective predictor for medium-term neurodevelopment. What is Known: • Prematurity is a major risk factor for adverse neurodevelopment. • The validation of clinical tools for psychomotor outcome prediction may aid to identify high-risk preterm infants who might benefit from early interventions. What is New: • In infants without major brain lesions, predischarge CrSO 2 correlates with psychomotor outcome at 6 months ca but not later, indicating a short time predictability., (© 2022. The Author(s).)

Nutrition in the first 1000 days of life is essential to ensure appropriate growth rates, prevent adverse short- and long-term outcomes, and allow physiologic neurocognitive development. Appropriate management of early nutritional needs is particularly crucial for preterm infants. Although the impact of early nutrition on health outcomes in preterm infants is well established, evidence-based recommendations on complementary feeding for preterm neonates and especially extremely low birth weight and extremely low gestational age neonates are still lacking. In the present position paper we performed a narrative review to summarize current evidence regarding complementary feeding in preterm neonates and draw recommendation shared by joint societies (SIP, SIN and SIGENP) for paediatricians, healthcare providers and families with the final aim to reduce the variability of attitude and timing among professionals., (© 2022. The Author(s).)

Background: Preterm infants are at enhanced risk of brain injury due to altered cerebral haemodynamics during postnatal transition. This observational study aimed to assess the clinical determinants of transitional cerebrovascular reactivity and its association with intraventricular haemorrhage (IVH)., Methods: Preterm infants <32 weeks underwent continuous monitoring of cerebral oxygenation and heart rate over the first 72 h after birth. Serial cranial and cardiac ultrasound assessments were performed to evaluate the ductal status and to diagnose IVH onset. The moving correlation coefficient between cerebral oxygenation and heart rate (TOHRx) was calculated. Linear mixed-effect models were used to analyse the impact of relevant clinical variables on TOHRx. The association between TOHRx and IVH development was also assessed., Results: Seventy-seven infants were included. A haemodynamically significant patent ductus arteriosus (hsPDA) (β = 0.044, 95% CI: 0.007-0.081) and ongoing dopamine treatment (β = 0.096, 95% CI: 0.032-0.159) were associated with increasing TOHRx, indicating impaired cerebrovascular reactivity. A significant association between TOHRx, mean arterial blood pressure (β = -0.004, 95% CI: -0.007, -0.001) and CRIB-II score (β = 0.007, 95% CI: 0.001-0.015) was also observed. TOHRx was significantly higher in infants developing high-grade IVH compared to those without IVH., Conclusions: Dopamine treatment, low blood pressure, hsPDA and high CRIB-II are associated with impaired cerebrovascular reactivity during postnatal transition, with potential implications on IVH development., Impact: The correlation coefficient between cerebral oxygenation and heart rate (TOHRx) provides a non-invasive estimation of cerebrovascular reactivity, whose failure has a potential pathogenic role in the development of IVH in preterm infants. This study shows that cerebrovascular reactivity during the transitional period improves over time and is affected by specific clinical and therapeutic factors, whose knowledge could support the development of individualized neuroprotective strategies in at-risk preterm infants. The evidence of increased TOHRx in infants developing high-grade compared to low-grade or no IVH during the transitional period further supports the role of impaired cerebrovascular reactivity in IVH pathophysiology., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Human milk (HM) is the best feeding option for preterm infants; however, when mother's own milk (MOM) is not available, pasteurized donor human milk (DHM) is the best alternative. In this study, we profiled DHM microbiota (19 samples) using 16S rRNA amplicon sequencing and compared its compositional features with the MOM microbiota (14 samples) from mothers who delivered prematurely (PT-MOM). As a secondary study aim, we assessed the specific effect of pasteurization on the characteristics of the DHM microbiota. DHM showed significantly higher alpha diversity and significant segregation from PT-MOM. Compositionally, the PT-MOM microbiota had a significantly higher proportion of Staphylococcus than DHM, with Streptococcus tending to be and Pseudomonas being significantly overrepresented in DHM compared with the PT-MOM samples. Furthermore, pasteurization affected the HM microbiota structure, with a trend towards greater biodiversity and some compositional differences following pasteurization. This pilot study provided further evidence on the HM microbial ecosystem, demonstrating that the DHM microbiota differs from the PT-MOM microbiota, possibly due to inherent differences between HM donors and mothers delivering prematurely, and that pasteurization per se impacts the HM microbiota. Knowledge about HM microbiota needs to be acquired by investigating the effect of DHM processing to develop strategies aimed at improving DHM quality while guaranteeing its microbiological safety.

Background: Following preterm birth, the immature kidney is exposed to several harmful conditions, with an increased risk of renal impairment. We aimed to assess urinary biomarkers of renal function in very preterm infants during early nephrotoxic treatments., Methods: Infants ≤32 weeks' gestation and ≤1500 g were enrolled in this observational prospective study. Urine samples were collected on day 1(T1), 2-4(T2), 5-7(T3), 8-10(T4), 11-13(T5). The following urinary biomarkers were determined: osteopontin (uOPN), epidermal growth factor (uEGF), neutrophil gelatinase-associated lipocalin (uNGAL), cystatin C (uCysC). The infants were grouped according to their exposure to amikacin or ibuprofen during the study period and a between-group comparison of urinary biomarkers at each time point was performed., Results: Thirty-six infants were included. Urinary CysC, uOPN, and uNGAL rose significantly during ibuprofen or amikacin treatment, while no difference was observed for uEGF. After adjustment for possible influencing factors, amikacin administration was associated with higher uCysC at T1 (p = 0.007) and T2 (p = 0.016), whereas ibuprofen increased uOPN (p = 0.001) and uNGAL concentration (p = 0.009) at T3., Conclusion: Nephrotoxic therapies induce molecule-specific change patterns of renal function biomarkers in treated preterm infants. Serial assessments of these biomarkers may aid to identify neonates at risk of renal impairment and to develop tailored therapeutic approaches., Impact: Despite the wide use of nephrotoxic therapies in neonatal settings, little is known on their effect on renal function biomarkers in preterm infants. This study describes molecule-specific change patterns of urinary biomarkers during ibuprofen and amikacin administration, suggesting underlying pathophysiological effects on renal function. Given their low analytical costs and non-invasive collection, the urinary biomarkers investigated in this study represent a promising strategy for serial monitoring of renal function in at-risk neonates and may aid the early detection of renal function impairment at different kidney levels during nephrotoxic treatments., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Despite the well-recognized importance of proper gut microbiota assembly for the child's future health, the connections between the early-life gut microbiota and neurocognitive development in humans have not been thoroughly explored so far. In this pilot observational study, we aimed to unveil the relation between dynamic succession of the gut microbiota in very low birth weight infants during the first month of life and their neurodevelopment, assessed at 24-month corrected age. According to our data, the early-life gut microbiota of preterm infants with normal vs. impaired neurodevelopment followed distinct temporal trajectories with peculiar compositional rearrangements. In this context, early Bifidobacterium deficiency appears to be a negative biomarker of adverse neurological outcomes., Conclusion: Our data might pave the way for future in-depth studies focusing on the potential impact of bifidobacteria or specific microbiota patterns on neonatal neurodevelopment and lay the foundation for microbiome-based clinical practices to modulate altered profiles and improve long-term health., What Is Known: • Preterm infants are at increased risk for adverse neurological outcomes and gut microbiota dysbiosis. • The gut microbiota and the nervous system share critical developmental windows in early life., What Is New: • The absence of Bifidobacterium at 30 days of life in preterm infants is associated with neurodevelopmental impairment in early childhood. • The administration of Bifidobacterium strains could promote optimal neurocognitive development in fragile infants., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may manifest as a life-threatening respiratory infection with systemic complications. Clinical manifestations among children are generally less severe than those seen in adults, but critical cases have increasingly been reported in infants less than 1 year of age. We report a severe case of neonatal COVID-19 requiring intensive care and mechanical ventilation, further complicated by a multidrug-resistant Enterobacter asburiae super-infection. Chest X-rays, lung ultrasound, and chest computed tomography revealed extensive interstitial pneumonia with multiple consolidations, associated with persistent increased work of breathing and feeding difficulties. SARS-CoV-2 RNA was detected in respiratory specimens and stools, but not in other biological samples, with a rapid clearance in stools. Serological tests demonstrated a specific SARS-CoV-2 antibody response mounted by the neonate and sustained over time. The therapeutic approach included the use of enoxaparin and steroids which may have contributed to the bacterial complication, underlying the challenges in managing neonatal COVID-19, where the balance between viral replication and immunomodulation maybe even more challenging than in older ages., (© 2021 Wiley Periodicals LLC.)

Young children use gestures to practice communicative functions that foster their receptive and expressive linguistic skills. Studies investigating the use of gestures by late talkers are limited. This study aimed to investigate the use of gestures and gesture-word combinations and their associations with word comprehension and word and sentence production in late talkers. A further purpose was to examine whether a set of individual and environmental factors accounted for interindividual differences in late talkers' gesture and gesture-word production. Sixty-one late talkers, including 35 full-term and 26 low-risk preterm children, participated in the study. Parents filled out the Italian short forms of the MacArthur-Bates Communicative Development Inventories (MB-CDI), "Gesture and Words" and "Words and Sentences" when their children were 30-months-old, and they were then invited to participate in a book-sharing session with their child. Children's gestures and words produced during the book-sharing session were transcribed and coded into CHAT of CHILDES and analyzed with CLAN. Types of spontaneous gestures (pointing and representational gestures) and gesture-word combinations (complementary, equivalent, and supplementary) were coded. Measures of word tokens and MLU were also computed. Correlational analyses documented that children's use of gesture-word combinations, particularly complementary and supplementary forms, in the book-sharing session was positively associated with linguistic skills both observed during the session (word tokens and MLU) and reported by parents (word comprehension, word production, and sentence production at the MB-CDI). Concerning individual factors, male gender was negatively associated with gesture and gesture-word use, as well as with MB-CDI action/gesture production. In contrast, having a low-risk preterm condition and being later-born were positively associated with the use of gestures and pointing gestures, and having a family history of language and/or learning disorders was positively associated with the use of representational gestures. Furthermore, a low-risk preterm status and a higher cognitive score were positively associated with gesture-word combinations, particularly complementary and supplementary types. With regard to environmental factors, older parental age was negatively associated with late talkers' use of gestures and pointing gestures. Interindividual differences in late talkers' gesture and gesture-word production were thus related to several intertwined individual and environmental factors. Among late talkers, use of gestures and gesture-word combinations represents a point of strength promoting receptive and expressive language acquisition.

Down syndrome (DS) is characterised by several clinical features including intellectual disability (ID) and craniofacial dysmorphisms. In 1976, Jackson and coll. identified a checklist of signs for clinical diagnosis of DS; the utility of these checklists in improving the accuracy of clinical diagnosis has been recently reaffirmed, but they have rarely been revised. The purpose of this work is to reassess the characteristic phenotypic signs and their frequencies in 233 DS subjects, following Jackson's checklist. 63.77% of the subjects showed more than 12 signs while none showed less than 5, confirming the effectiveness of Jackson's checklist for the clinical diagnosis of DS. An association between three phenotypic signs emerged, allowing us to distinguish two sub-phenotypes: Brachycephaly, short and broad Hands, short Neck (BHN), which is more frequent, and "non-BHN". The strong association of these signs might be interpreted in the context of the growth defects observed in DS children suggesting decreased cell proliferation. Lastly, cognitive assessments were investigated for 114 subjects. The lack of association between the presence of a physical sign or the number of signs present in a subject and cognitive skills disproves the stereotype that physical characteristics are predictive of degree of ID., (© 2022. The Author(s).)

The study was aimed at describing potential indirect effects of pandemic-related measures on very-low-birthweight infants in four Italian NICUs. No overall change in late-onset sepsis (LOS) and necrotizing enterocolitis was documented. However, in the NICU where baseline LOS rate was high, a significant reduction in LOS incidence was recorded. Conclusion: COVID-19-related implementation of NICU hygiene policies is likely to reduce the occurrence of LOS in high-risk settings. What is Known: • COVID-19 pandemic has disrupted routine care in Neonatal Intensive Care Units (NICUs), mostly by tightening infection control measures and restricting parental presence in the NICU. • Beyond the described psychological impact of COVID-19 related measures on healthcare workers and NICU families, their consequences in terms of preterm infants' clinical outcomes have not been described in detail yet. What is New: • Strengthened infection-control measures do not seem to have an overall influence on the incidence of necrotising enterocolitis and late-onset sepsis in very-low-birth-weight infants. • However, the implementation of these measures appears to reduce the occurrence of late-onset sepsis in settings where the baseline incidence of the disease is high., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Early parental interventions in the Neonatal Intensive Care Units (NICUs) have beneficial effects on preterm infants' short and long-term outcomes. The aim of this study was to investigate the effects of Early Vocal Contact (EVC)-singing and speaking-on preterm infants' vagal activity and autonomic nervous system (ANS) maturation., Methods: In this multi-center randomized clinical trial, twenty-four stable preterm infants, born at 25-32 weeks gestational age, were randomized to either the EVC group or control group, where mothers did not interact with the babies but observed their behavior. Heart Rate Variability (HRV) was acquired before intervention (pre-condition), during vocal contact, and after it (post condition)., Results: No significant effect of the vocal contact, singing and speaking, was found in HRV when the intervention group was compared to the control group. However, a significant difference between the singing and the pre and post conditions, respectively, preceding and following the singing intervention, was found in the Low and High Frequency power nu, and in the low/high frequency features ( p = 0.037). By contrast, no significant effect of the speaking was found., Conclusions: Maternal singing, but not speaking, enhances preterm infants' vagal activity in the short-term, thus improving the ANS stability. Future analyses will investigate the effect of enhanced vagal activity on short and long-term developmental outcomes of preterm infants in the NICU.

Free radicals play a role of paramount importance in the development of neonatal brain injury. Depending on the pathophysiological mechanisms underlying free radical overproduction and upon specific neonatal characteristics, such as the GA-dependent maturation of antioxidant defenses and of cerebrovascular autoregulation, different profiles of injury have been identified. The growing evidence on the detrimental effects of free radicals on the brain tissue has led to discover not only potential biomarkers for oxidative damage, but also possible neuroprotective therapeutic approaches targeting oxidative stress. While a more extensive validation of free radical biomarkers is required before considering their use in routine neonatal practice, two important treatments endowed with antioxidant properties, such as therapeutic hypothermia and magnesium sulfate, have become part of the standard of care to reduce the risk of neonatal brain injury, and other promising therapeutic strategies are being tested in clinical trials. The implementation of currently available evidence is crucial to optimize neonatal neuroprotection and to develop individualized diagnostic and therapeutic approaches addressing oxidative brain injury, with the final aim of improving the neurological outcome of this population.

Background: Congenital brain tumors are extremely rare in the neonatal population, and often associated with a poor prognosis. The diagnostic suspicion is often aroused at antenatal scans or postnatally, if clinical signs and symptoms of increased intracranial pressure become evident. We present a case of definitely congenital glioblastoma multiforme incidentally diagnosed in a preterm infant, aiming to raise clinical awareness on this condition and to highlight the challenges of the related diagnostic work-up., Case Presentation: This female infant was born at 31 weeks' gestation after an uneventful pregnancy. No abnormalities were detected at antenatal ultrasound scans and genetic tests. Head circumference at birth was on the 25th centile. A routine brain ultrasound scan performed on day 1 revealed a large, inhomogeneous lesion in the right cerebral hemisphere, with contralateral midline shift, which was confirmed by brain magnetic resonance imaging (MRI). Eye fundus and routine blood exams, including platelets count, coagulation screening and C-reactive protein, were normal. Given the high risk of complications, surgical biopsy of the lesion was temporarily hold and a daily sonographic follow-up was undertaken. Although head circumference growth was steady on the 25th centile, progressive changes of the lesion were detected by cranial ultrasound. The repeat MRI scans showed a significant enlargement of the mass, with contralateral midline shift and signs of intralesional and intraventricular bleeding. In view of this worsening, surgical resection was performed. The histological examination of the lesion biopsy documented a GFAP+ highly cellular neoplasm, with no mutation on SMARCB1 gene. At the molecular analysis, mutations on IDH and H3F3A genes were absent, whereas MGMT promoter was unmethylated. The diagnosis was grade IV glioblastoma IDH wild-type., Conclusions: Congenital glioblastoma multiforme is an extremely rare but highly aggressive neoplasm. Since intralesional biopsy is not often feasible in affected neonates, knowledge of the associated clinical and neuroradiological features is particularly important, as they can also add useful information on the neoplasm behavior. Specimens from open surgical resection allow to perform a definite histological analysis and an extended molecular characterization, with relevant prognostic implications., (© 2021. The Author(s).)

Several qualitative and quantitative features of parental speech input support children's language development and may play a critical role in improving such process in late talkers. Parent-implemented interventions targeting late-talkers have been developed to promote children's language outcomes by enhancing their linguistic environment, i.e., parental speech input. This study investigated the effect of a parent-implemented intervention in increasing late talkers' expressive skills through modifications in structural and functional features of parental speech input. Forty-six thirty-one-month-old late talkers differing in their birth condition (either low-risk preterm or full-term) participated in the study with a parent; 24 parent-child dyads received a parent-implemented intervention centered on dialogic reading and focused stimulation techniques, whereas the other 22 dyads constituted the control group. At pre- and post-intervention, dyads took part in a parent-child shared book-reading session and both parental and child's speech measures were collected and examined. Results showed that the intervention positively affected parents' use of responses and expansions of children's verbal initiatives, as well as the parental amount of talking over reading, whereas no structural features of parental input resulted modified. Mediation analyses pointed out that the intervention indirectly enhanced late-talkers' use of verbal types and tokens through changes in parental use of expansions and amount of talking over reading. As birth status was entered as a covariate in the analysis, these findings can be extended to children with different gestational age. We conclude that the parent-implemented intervention was effective in supporting late-talkers' gains in language development as a cascade result of the improvements in parental contingency and dialogic reading abilities. These promising findings suggest to examine not only children and parental outcomes but also the intervention mechanisms promoting changes in late-talkers' language development as a clearer view on such process can inform the development of feasible, ecological and effective programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Suttora, Zuccarini, Aceti, Corvaglia, Guarini and Sansavini.)

Perfluoroalkyl substances (PFASs) are environmental contaminants that have been shown to exert toxic effects, which are dependent upon concentration, in animals and humans. No specific data on the exposure of preterm infants to PFASs are available. We aimed to quantify the potential exposure of preterm infants to PFASs through human milk (HM), to be compared to the exposure data recently reported for infants by EFSA. The amount of PFASs in ten preterm (PHM) and ten donor HM (DHM) samples was evaluated, and the expected daily intake (EDI) at full enteral feeding was calculated. This EDI was compared to the mean and the 95 th centile dietary exposure ranges at the lower bound for infants issued by EFSA. The calculated median EDI for total PFASs was 20.72 ng/kg/day (range 10.72-107.84) for PHM and 17.92 ng/kg/day (range 6.4-28.96) for DHM, which were both higher than mean exposure ranges reported for infants (2.4-12.2 ng/kg/day). The calculated EDI for DHM was far more similar to the 95 th centile (4.5-27.9 ng/kg/day) dietary exposure ranges. For PHM samples, higher EDI values were obtained, with 4 out of 10 samples exceeding the upper limit of the 95 th centile range.Conclusion: The exposure of preterm infants to PFASs through HM feeding might exceed reference values reported for older and healthier infants. Given the immunological and developmental vulnerability of preterm infants, the risks related to their exposure to PFASs should be further investigated, also focusing on how maternal exposure and subsequent transfer through HM feeding can be reduced. What is Known: • Perfluoroalkyl substances (PFASs) are environmental contaminants that have been shown to exert toxic effects, which are dependent upon concentration, in animals and humans. The EFSA has recently issued reference values for PFASs exposure for different age groups. • Infants might be exposed to PFASs prenatally, as these substances can cross the placenta, and postnatally, through breastfeeding. No specific data about exposure of preterm infants through human milk (HM) feeding are currently available. What is New: • The exposure of preterm infants to PFASs through HM feeding might exceed reference values reported for older and healthier infants. • Given the immunological and developmental vulnerability of preterm infants, the risks related to their exposure to PFASs deserve further investigation. As HM represents the optimal feeding for preterm infants, it will be fundamental to focus on how maternal exposure and subsequent transfer through HM feeding can be reduced., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose Wide interindividual variability characterizes language development in the general and at-risk populations of up to 3 years of age. We adopted a complex approach that considers multiple aspects of lexical and grammatical skills to identify language profiles in low-risk preterm and full-term children. We also investigated biological and environmental predictors and relations between language profiles and cognitive and motor skills. Method We enrolled 200 thirty-month-old Italian-speaking children-consisting of 100 low-risk preterm and 100 comparable full-term children. Parents filled out the Italian version of the MacArthur-Bates Communicative Development Inventories Infant and Toddler Short Forms (word comprehension, word production, and incomplete and complete sentence production), Parent Report of Children's Abilities-Revised (cognitive score), and Early Motor Questionnaire (fine motor, gross motor, perception-action, and total motor scores) questionnaires. Results A latent profile analysis identified four profiles: poor (21%), with lowest receptive and expressive vocabulary and absent or limited word combination and phonological accuracy; weak (22.5%), with average receptive but limited expressive vocabulary, incomplete sentences, and absent or limited phonological accuracy; average (25%), with average receptive and expressive vocabulary, use of incomplete and complete sentences, and partial phonological accuracy; and advanced (31.5%), with highest expressive vocabulary, complete sentence production, and phonological accuracy. Lower cognitive and motor scores characterized the poor profile, and lower cognitive and perception-action scores characterized the weak profile. Having a nonworking mother and a father with lower education increased the probability of a child's assignment to the poor profile, whereas being small for gestational age at birth increased it for the weak profile. Conclusions These findings suggest a need for a person-centered and cross-domain approach to identifying children with language weaknesses and implementing timely interventions. An online procedure for data collection and data-driven analyses based on multiple lexical and grammatical skills appear to be promising methodological innovations. Supplemental Material https://doi.org/10.23641/asha.14818179.

Patent ductus arteriosus (PDA) is common among extremely preterm infants. In selected cases, surgical PDA ligation may be required. The timing for PDA ligation may depend upon a variety of factors, with potential clinical implications. We aimed to investigate the impact of different surgical PDA managements on ligation timing and neonatal outcomes. Inborn infants < 32 weeks of gestation and < 1500 g admitted at two tertiary Neonatal Intensive Care Units that underwent PDA ligation between 2007 and 2018 were enrolled in this retrospective cohort study and split into the following groups based on their surgical management: on-site bedside PDA ligation (ONS) vs. referral to an off-site pediatric cardiac surgery (OFS). Neonatal characteristics, surgical timing, and clinical outcomes of the enrolled infants were compared between the groups. Multivariate analysis was performed to evaluate the impact of PDA ligation timing on significantly different outcomes. Seventy-eight neonates (ONS, n = 39; OFS, n = 39) were included. Infants in the ONS group underwent PDA ligation significantly earlier than those in the OFS group (median age 12 vs. 36 days, p < 0.001) with no increase in postoperative mortality and complications. The multivariate analysis revealed a significant association between PDA ligation timing, late-onset sepsis prevalence (OR 1.045, 0.032), and oxygen need at discharge (OR 1.037, p = 0.025).Conclusions: Compared with off-site surgery, on-site bedside ligation allows an earlier surgical closure of PDA, with no apparent increase in mortality or complications. Earlier PDA ligation may contribute to reduced rates of late-onset sepsis and post-discharge home oxygen therapy, with possible cost-benefit implications. What is known: • Ineffective or contraindicated pharmacological closure of a hemodynamically significant PDA may require a surgical ligation. • Available literature comparing the effect of early vs. late PDA ligation on the main neonatal morbidities has yield contrasting results. What is new: • The availability of a cardiac surgery service performing bedside PDA ligation allows an earlier intervention compared to patient referral to an off-site center, with no difference in postoperative mortality and complications compared to off-site surgery. • Earlier PDA ligation was associated with a lower prevalence of late-onset sepsis and of oxygen need at discharge, with possible cost-benefit implications.

Necrotizing enterocolitis (NEC) is a gut inflammatory disorder which constitutes one of the leading causes of morbidity and mortality for preterm infants. The pathophysiology of NEC is yet to be fully understood; several observational studies have led to the identification of multiple factors involved in the pathophysiology of the disease, including gut immaturity and dysbiosis of the intestinal microbiome. Given the complex interactions between microbiota, enterocytes, and immune cells, and the limited access to fetal human tissues for experimental studies, animal models have long been essential to describe NEC mechanisms. However, at present there is no animal model perfectly mimicking human NEC; furthermore, the disease mechanisms appear too complex to be studied in single-cell cultures. Thus, researchers have developed new approaches in which intestinal epithelial cells are exposed to a combination of environmental and microbial factors which can potentially trigger NEC. In addition, organoids have gained increasing attention as promising models for studying NEC development. Currently, several in vitro models have been proposed and have contributed to describe the disease in deeper detail. In this paper, we will provide an updated review of available in vitro models of NEC and an overview of current knowledge regarding its molecular underpinnings.

Optimal nutrition is essential to improve short- and long-term outcomes in newborns with congenital heart disease (CHD). Nevertheless, several issues on nutritional management and concerns about the potential risk of complications related to enteral feeding exist. This narrative review aims to summarize and discuss the available literature on enteral feeding in term infants with CHD. A wide variability in feeding management exists worldwide. Emerging approaches to improve nutritional status and outcomes in infants with CHD include: implementation of a standardized enteral feeding protocol, both preoperative and postoperative, clearly defining time of initiation and advancement of enteral feeds, reasons to withhold, and definitions of feeding intolerance; early minimal enteral feeding; enteral feeding in stable term infants on hemodynamic support; evaluation of enteral feeding in term infants with umbilical arterial catheters and during prostaglandin infusion; assessment and support of oro-motor skills; and promotion and support of breastfeeding and provision of mother's own milk or donor milk when mother's own milk is not available. As evidence from term infants is scarce, available observations and recommendations partially rely on studies in preterm infants. Thus, well-designed studies assessing standardized clinically relevant outcomes are needed to provide robust evidence and shared recommendations and practices.

We aimed to evaluate the reliability of lung ultrasound (LU) to predict admission to the neonatal intensive care unit (NICU) for transient neonatal tachypnoea or respiratory distress syndrome in infants born by caesarean section (CS). A prospective, observational, single-centre study was performed in the delivery room and NICU of Sant'Orsola-Malpighi Hospital in Bologna, Italy. Term and late-preterm infants born by CS were included. LU was performed at 30' and 4 h after birth. LU appearance was graded according to a previously validated three-point scoring system (3P-LUS: type-1, white lung; type-2, black/white lung; type-3, normal lung). Full LUS was also calculated. One hundred infants were enrolled, and seven were admitted to the NICU. The 5 infants with bilateral type-1 lung at birth were all admitted to the NICU. Infants with type-2 and/or type-3 lung were unlikely to be admitted to the NICU. Mean full-LUS was 17 in infants admitted to the NICU, and 8 in infants not admitted. In two separate binary logistic regression models, both the 3P- and the full LUS proved to be independently associated with NICU admission (OR [95% CI] 0.001 [0.000-0.058], P = .001, and 2.890 [1.472-5.672], P = .002, respectively). The ROC analysis for the 3P-LUS yielded an AUC of 0.942 (95%CI, 0.876-0.979; P<.001), while ROC analysis for the full LUS yielded an AUC of 0.978 (95%CI, 0.926-0.997; P<.001). The AUCs for the two LU scores were not significantly different (p = .261).Conclusion: the 3P-LUS performed 30 min after birth proved to be a reliable tool to identify, among term and late preterm infants born to CS, those who will require NICU admission for transient neonatal tachypnoea or respiratory distress syndrome. What is known • Lung ultrasound (LU) has become an attractive diagnostic tool in neonatal settings, and guidelines on point-of-care LU in the neonatal intensive care unit (NICU) have been recently issued. • LU is currently used for diagnosing several neonatal respiratory morbidities and has been also proposed for predicting further intervention, such as NICU admission, need for surfactant treatment or mechanical ventilation in preterm infants. What is new • LU performed 30' after birth and evaluated through a simple three-point scoring system represents a reliable tool to identify, among term and late preterm infants born to caesarean section, those with transient neonatal tachypnoea or respiratory distress syndrome who will require NICU admission. • LU performed in the neonatal period confirms its potential role in ameliorating routine neonatal clinical management.

Background: Recent evidence supports a role of probiotics in preventing necrotizing enterocolitis (NEC) in preterm infants., Methods: A systematic review and network meta-analysis of randomized controlled trials (RCTs) on the role of probiotics in preventing NEC in preterm infants, focusing on the differential effect of type of feeding, was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A random-effects model was used; a subgroup analysis on exclusively human milk (HM)-fed infants vs. infants receiving formula (alone or with HM) was performed., Results: Fifty-one trials were included (10,664 infants, 29 probiotic interventions); 31 studies (19 different probiotic regimens) were suitable for subgroup analysis according to feeding. In the overall analysis, Lactobacillus acidophilus LB revealed the most promising effect for reducing NEC risk (odds ratio (OR), 0.03; 95% credible intervals (CrIs), 0.00-0.21). The subgroup analysis showed that Bifidobacterium lactis Bb-12/B94 was associated with a reduced risk of NEC stage ≥2 in both feeding type populations, with a discrepancy in the relative effect size in favour of exclusively HM-fed infants (OR 0.04; 95% CrIs <0.01-0.49 vs. OR 0.32; 95% CrIs 0.10-0.36)., Conclusions: B. lactis Bb-12/B94 could reduce NEC risk with a different size effect according to feeding type. Of note, most probiotic strains are evaluated in few trials and relatively small populations, and outcome data according to feeding type are not available for all RCTs. Further trials are needed to confirm the present findings.

Parent-implemented language interventions have been used for children with expressive language delays, but no study has yet been carried out using this intervention for low-risk preterm children. The current study examined the effect of a parent-implemented dialogic book reading intervention, determining also whether the intervention differently impacted low-risk preterm and full-term children. Fifty 31-month-old late talkers with their parents participated; 27 late talkers constituted the intervention group, and 23 constituted the control group. The overall results indicated that more children in the intervention group showed partial or full recovery of their lexical expressive delay and acquired the ability to produce complete sentences relative to the control group. Concerning full-term late talkers, those in the intervention group showed a higher daily growth rate of total words, nouns, function words, and complete sentences, and more children began to produce complete sentences relative to those in the control group. Concerning low-risk preterm late talkers, children in the intervention group increased their ability to produce complete sentences more than those in the control group. We conclude that a parent-focused intervention may be an effective, ecological, and cost-effective program for improving expressive lexical and syntactic skills of full-term and low-risk preterm late talkers, calling for further studies in late talkers with biological vulnerabilities.

The perspective proposed by this article will focus on perinatal palliative care as a strategy for improving the quality of life of neonates with life-limiting conditions when extending the patient's life is no longer the goal of care. This manuscript reports the creation of an innovative program of perinatal palliative care called "Percorso Giacomo" (Giacomo's Pathway) at Sant'Orsola Hospital in Bologna, Italy in 2013. Key features include interdisciplinary collaboration between professionals from obstetrics, neonatology and other specialties aiming to reach the most detailed fetal and neonatal diagnosis and prognosis; communication and engagement with the family to discuss goals of care and prepare a birthing plan that follows the family's desires and expectations; and personalized care to achieve comfort for each newborn and support for families according to their social, cultural, and religious backgrounds., (Copyright © 2020 Locatelli, Corvaglia, Simonazzi, Bisulli, Paolini and Faldella.)

Among children in the third year of life, late talkers comprise from 9% to 20%. This range seems to increase when addressing preterm children. This study examined video-recorded child spontaneous speech during parent-child book sharing as well as linguistic skills reported through the MacArthur Bates Communicative Development Inventories (MB-CDI) Short Form in 61 late talkers aged 30 months old (26 low-risk preterm, 8 females; 35 full-term, 12 females). Differences between low-risk preterm and full-term late talkers in child language measures and parental speech input were tested, as were the roles of child and parent factors on child language. Low-risk preterm and full-term late talkers showed similar speech and language skills. Similarly, no differences were found in measures of parental speech between groups. Child cognitive score, chronological age, and low-risk preterm status were positively associated with lexical diversity, rate, and composition of child speech production, whereas family history for language and/or learning disorders as well as parent measures of lexical diversity, rate, and grammatical complexity were negatively associated with the above child variables. In addition, child cognitive score and low-risk preterm status were positively associated with the MB-CDI measures of word and sentence production. Findings are discussed in terms of the need of good practices when following up on low-risk preterm children and of interventions targeting parents' input to preterm and full-term late talkers.

Key Points: Non-invasive simultaneous multiparametric monitoring allows the in vivo evaluation of cerebral and cardiovascular haemodynamic responses to different types of recurrent episodes of intermittent hypoxia and/or bradycardia, also defined as cardio-respiratory events (CRE), in preterm neonates during postnatal transition. By decreasing left cardiac output, bradycardia further contributes to cerebral hypoxia during CRE. The presence of a haemodynamically significant patent ductus arteriosus results in a deeper impairment of cerebral oxygen status in response to CRE, whereas the brain-sparing remodelling of the fetal circulation resulting from placental insufficiency is associated with more favourable haemodynamic responses to intermittent hypoxia. During transition, the haemodynamic impact of CRE is influenced not only by the event type, but also by specific clinical features; this highlights the importance of developing individualized approaches to reduce the hypoxic burden in this delicate phase., Abstract: The present observational prospective study aimed to investigate cerebral and cardiovascular haemodynamic responses to different types of cardio-respiratory events (CRE) in preterm infants during postnatal transition, as well as evaluate the impact of relevant clinical characteristics. Infants with gestational age (GA) <32 weeks and/or birth weight <1500 g were enrolled after birth. Cerebral oxygenation index (cTOI), fractional oxygen extraction (cFTOE), cardiac output (CO), cardiac contractility (iCON) and systemic vascular resistances (sVR) were simultaneously monitored over the first 72 h by near-infrared spectroscopy and electrical velocimetry. CRE were clustered into isolated bradycardia (IB), isolated desaturation (ID) and combined desaturation/bradycardia (DB). For each parameter, percentage changes from baseline (%Δ) were calculated. The impact of different CRE types and clinical variables on %Δ was evaluated with generalized estimating equations. In total, 1426 events were analysed. %ΔcTOI significantly differed among ID, IB and DB (P < 0.001), with the latter showing the greatest drop. %ΔcFTOE decreased significantly during DB (P < 0.001) and ID (P < 0.001) compared to IB. DB and IB were associated with more negative %ΔCO (P < 0.001) and more positive %ΔsVR (P < 0.001) compared to ID. A slight iCON reduction was observed during DB compared to ID (P = 0.043). Antenatal umbilical Doppler impairment, GA and the presence of a haemodynamically significant patent ductus arteriosus had a significant independent impact on %ΔcTOI, %ΔcFTOE and %ΔCO. During the transitional period, the haemodynamic responses to CRE are influenced by the event type and by specific neonatal characteristics, suggesting the importance of targeted individualized approaches for minimizing the risk of cerebral injury in the preterm population., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Background: Preterm infants often require red blood cell (RBC) transfusions, which may impair splanchnic hemodynamics, thus predisposing to necrotizing enterocolitis (NEC). The aim of this study was to evaluate whether RBC transfusions alter splanchnic oxygenation patterns in response to enteral feeding in this population., Materials and Methods: Preterm neonates (gestational age < 32 weeks and/or birth weight < 1500 g) requiring RBC transfusions for anemia underwent a 12-hour Near Infrared Spectroscopy monitoring of splanchnic (SrSO 2 ) and cerebral (CrSO 2 ) oxygenation, including the transfusion period, one feed before and one after. Splanchnic-cerebral oxygenation ratio (SCOR) was also calculated. Patterns of CrSO 2 , SrSO 2 , and SCOR changes from baseline (Δ) in response to feed before and after transfusion were analyzed., Results: Twenty neonates were enrolled; none of them developed any gastrointestinal complication within 48 hours after transfusion. Pre-transfusion ΔSrSO 2 and ΔSCOR increased significantly in response to feeding; on the contrary, a significant post-prandial decrease of ΔSrSO 2 and ΔSCOR occurred after transfusion (p < 0.05). No difference in pre- and post-transfusion ΔCrSO 2 patterns was observed., Conclusions: In preterm infants, RBC transfusions may alter splanchnic oxygenation response to enteral feeds. Whether these changes are involved in the pathogenesis of transfusion-associated NEC has to be evaluated in further larger trials., (© 2020 AABB.)

Background: The transitional period, defined as the first 72 h after preterm birth, is often characterized by a significant hemodynamic instability, which represents an important risk factor for such neurological complications of prematurity as intraventricular hemorrhage (IVH). The impairment of cerebral autoregulation plays a key role in the pathogenesis of IVH, whose incidence is highest during the transitional period. This pilot study aimed to evaluate whether patterns of cerebral autoregulation and oxygenation differ in relation to IVH development in very preterm infants during the transitional period. Methods: Infants <32 weeks' gestation were enrolled within 12 h from birth. A simultaneous monitoring of cerebral oxygenation (CrSO 2 ) by near-infrared spectroscopy and of heart rate and peripheral oxygen saturation by pulse oximetry was performed over the first 72 h. Cerebral fractional oxygen extraction (cFTOE) and tissue oxygenation-heart rate reactivity index (TOHRx), which represents a marker of cerebrovascular reactivity, were calculated. Daily cranial and cardiac ultrasound scans were performed, in order to assess the hemodynamic status and to detect a possible IVH onset. CrSO 2 and cFTOE, clustered on 6-hour epochs, were compared between infants who developed IVH during the study period and those who did not. A between-group comparison of TOHRx before and after IVH detection was also performed. Results: Twenty preterm infants with a median gestational age of 27 weeks (interquartile range, IQR: 25-30 weeks) and median birth weight of 895 g (IQR: 822-1208 g) were enrolled. Of these, 8 developed IVH. The median age at IVH detection was 40 h (IQR: 30-48 h). Pre-IVH TOHRx was significantly higher compared to matched control periods ( p <0.001). CrSO 2 was significantly lower from 12 to 30 h and from 42 h onwards in cases compared to controls; however, a temporary CrSO 2 rise preceded IVH detection. Similarly, cFTOE was significantly higher in IVH infants from 12 to 30 h and from 48 to 72 h, with a transient decrease between the two periods. Conclusions: In preterm infants during the transitional period, the development of IVH is preceded by transient changes in cerebral oxygenation and oxygen extraction which, in turn, may underlie an early impairment of cerebral autoregulation. Larger studies are needed to confirm these preliminary findings., (Copyright © 2020 Cimatti, Martini, Galletti, Vitali, Aceti, Frabboni, Faldella and Corvaglia.)

There is evidence that preterm infants of migrant mothers are at a higher risk of adverse perinatal outcomes than those of native-born mothers, and that human milk feeding is beneficial to infants' neurodevelopment. Using the United Nations Human Development Index (HDI) to classify mother's country of origin, we investigated whether type of neonatal feeding (human milk vs. mixed milk vs. exclusive formula milk) affected preterm newborn neurodevelopment varying across different HDI categories (Italian native-born vs. high HDI migrant vs. low HDI migrant) up to 2 years of age. Neurodevelopment of 530 infants born in Italy at ≤32 weeks of gestational age and/or weighing <1500 g was measured at 3-, 6-, 9-, 12-, 18-, and 24-months corrected age (CA) using the revised Griffiths Mental Development Scale 0-2 years. The trajectories of the general developmental quotient and its five subscales were estimated using mixed models. At 24-months CA only preterm infants of low HDI migrant mothers and fed exclusive formula milk showed moderate neurodevelopment impairment, with lower developmental trajectories of eye-hand coordination, performance, and personal-social abilities. Migrant mothers from low HDI countries and their preterm infants should be targeted by specific programs supporting maternal environment, infant development, and human or mixed milk neonatal feeding. Future research should focus on a deeper understanding of the mechanisms through which type of feeding and mother migrant conditions interact in influencing preterm infants' neurodevelopment.

Background: This systematic review summarizes available literature regarding complementary feeding (CF) in preterm infants, with or without comorbidities that may interfere with oral functions., Methods: A literature search was conducted in PubMed and the Cochrane Library. Studies relating to preterm infants (gestational age <37 weeks) were included in the analysis. Retrieved papers were categorized according to their main topic: CF timing and quality; clinical outcome; recommendations; strategies in infants with oral dysfunction., Results: The literature search in PubMed retrieved 6295 papers. Forty met inclusion criteria. The Cochrane search identified four additional study protocols, two related to studies included among PubMed search results, and two ongoing trials. Moreover, among 112 papers dealing with oral feeding, four aiming at managing CF in preterm infants with oral dysfunctions were identified., Conclusions: The available literature does not provide specific guidelines on the management of CF in preterm infants, who are generally weaned earlier than term infants. There is a paucity of data regarding the relationship between CF and growth/quality of growth and health outcomes in preterm infants. It could be suggested to start CF between five and eight months of chronological age if infants have reached three months corrected age and if they have acquired the necessary developmental skills. An individualized multidisciplinary intervention is advisable for preterm infants with oral dysfunctions.