Establishment of gut microbiota in term and preterm infants: evaluation by culture-independent methods

Background The establishment of a healthy gut microbiota (GM) in term and preterm infants can influence several clinical outcomes. The mechanisms driving GM establishment have been described partially, and the relationship between GM and microbiota from human milk (HM) and saliva is still a matter of debate. Little is known about GM in moderately preterm infants (MPIs). Aim of the study To characterize the establishment of GM, in relation to saliva and HM microbiota, in term and preterm infants, with a focus on MPIs. Methods Newborns were recruited at the Neonatal Unit of Sant’Orsola-Malpighi Hospital: • Group A: term infants, born to vaginal delivery, exclusively breastfed, not exposed to antibiotic/probiotic. • Group B: MPIs. • Group C: very preterm infants (ongoing sample collection). For each group, stools, HM and saliva were collected at different time points. Results Group A GM was dominated by Bifidobacteriaceae, followed by Enterobacteriaceae and Streptococcaceae. Streptococcaceae were the most represented family in HM, followed by Bifidobacteriaceae and Staphylococcaceae. Oral microbiota was largely dominated by Streptococcaceae. Microbiota from infant’s saliva, infant’s stools and HM clustered separately. Several OTUs were shared between at least two body sites. Group B GM of MPIs was dominated by Enterobacteriaceae, followed by Bifidobacteriaceae. Staphylococcaceae and Streptococcaceae were the most abundant families in HM, while Bifidobacteriaceae were low. Streptococcaceae dominated saliva microbiota. Longitudinal analysis of HM, stools and saliva microbiota showed some remarkable differences among infants, and even between twins, which could not be attributed to any clinical or environmental confounder. Conclusions Data from MPIs show that the characteristics of the establishment of GM in these infants are peculiar and more similar to very preterm than to term infants. The establishment of GM in MPIs is thus worth to be further explored, given the specific short- and long-term clinical risks of these infants

Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives

: 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

Describing communication profiles of low-risk preterm and full-term late talkers

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

Early-life gut microbiota and neurodevelopment in preterm infants: a narrative review

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 longterm 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

Probiotics for Preventing Necrotizing Enterocolitis in Preterm Infants: A Network Meta-Analysis

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\u20130.21). 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\u20130.49 vs. OR 0.32; 95% CrIs 0.10\u20130.36). 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

Altered intracellular ATP production by activated CD4+ T-cells in very preterm infants

Background. The neonatal immune system is not fully developed at birth; newborns have adequate lymphocytes counts but these cells lack function. Objective. To assess the activity of T-cells and the influence of the main perinatal factors in very preterm infants (birth weight < 1500 g). Design. Blood samples from 59 preterm infants (21/59 were dizygotic twins) were collected at birth and at 30 days of life to measure CD4+ T-cell activity using the ImmuKnow\u2122 assay. Fifteen healthy adults were included as a control group. Results. CD4+ T-cell activity was lower in VLBW infants compared with adults (p<0.001). Twins showed lower immune activity compared to singletons (p=0.005). Infants born vaginally showed higher CD4+ T-cell activity compared to those born by C-section (p=0.031); infants born after prolonged Premature Rupture of Membranes (pPROM) showed higher CD4+ T-cell activity at birth (p=0.002) compared to infants born without pPROM. Low CD4+ T-cell activity at birth is associated with necrotizing enterocolitis (NEC) in the first week of life (p=0.049). Conclusions. Preterm infants show a lack in CD4+ T-cell activity at birth. Perinatal factors such as intrauterine inflammation, mode of delivery, and zygosity can influence the adaptive immune activation capacity at birth and can contribute to exposing these infants to serious complications such as NEC

Neurodevelopmental Correlates of Brain Magnetic Resonance Imaging Abnormalities in Extremely Low-birth-weight Infants

Objective: To evaluate the relationship between impaired brain growth and structural brain abnormalities at term-equivalent age (TEA) and neurodevelopment in extremely low-birth-weight (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 gray matter items. Neurodevelopment was assessed at 6, 12, 18, and 24 months using the Griffiths scales. The independent associations between MRI subscores 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 = .040; b = -6.88, P = .049 respectively), social skills (b = -3.13, P = .019; b = -4.79, P = .049), and eye-hand coordination (b = -3.48, P = .009; b = -7.21, P = .045). Cystic white matter lesions were associated with poorer motor outcomes (b = -4.99, P = .027), while white matter signal abnormalities and corpus callosum thinning were associated with worse nonverbal cognitive performances (b = -6.42, P = .010; b = -6.72, P = .021, respectively). Deep gray 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, counseling of families, and development of targeted supportive interventions to improve neurodevelopment in ELBW neonates

Altered Intracellular ATP Production by Activated CD4+ T-Cells in Very Preterm Infants

Background. The neonatal immune system is not fully developed at birth; newborns have adequate lymphocytes counts but these cells lack function. Objective. To assess the activity of T-cells and the influence of the main perinatal factors in very preterm infants (birth weight < 1500 g). Design. Blood samples from 59 preterm infants (21/59 were dizygotic twins) were collected at birth and at 30 days of life to measure CD4+ T-cell activity using the ImmuKnow™ assay. Fifteen healthy adults were included as a control group. Results. CD4+ T-cell activity was lower in VLBW infants compared with adults (p<0.001). Twins showed lower immune activity compared to singletons (p=0.005). Infants born vaginally showed higher CD4+ T-cell activity compared to those born by C-section (p=0.031); infants born after prolonged Premature Rupture of Membranes (pPROM) showed higher CD4+ T-cell activity at birth (p=0.002) compared to infants born without pPROM. Low CD4+ T-cell activity at birth is associated with necrotizing enterocolitis (NEC) in the first week of life (p=0.049). Conclusions. Preterm infants show a lack in CD4+ T-cell activity at birth. Perinatal factors such as intrauterine inflammation, mode of delivery, and zygosity can influence the adaptive immune activation capacity at birth and can contribute to exposing these infants to serious complications such as NEC

Probiotics Prevent Late-Onset Sepsis in Human Milk-Fed, Very Low Birth Weight Preterm Infants: Systematic Review and Meta-Analysis

Growing evidence supports the role of probiotics in reducing the risk of necrotizing enterocolitis, time to achieve full enteral feeding, and late-onset sepsis (LOS) in preterm infants. As reported for several neonatal clinical outcomes, recent data have suggested that nutrition might affect probiotics\u2019 efficacy. Nevertheless, the currently available literature does not explore the relationship between LOS prevention and type of feeding in preterm infants receiving probiotics. Thus, the aim of this systematic review and meta-analysis was to evaluate the effect of probiotics for LOS prevention in preterm infants according to type of feeding (exclusive human milk (HM) vs. exclusive formula or mixed feeding). Randomized-controlled trials involving preterm infants receiving probiotics and reporting on LOS were included in the systematic review. Only trials reporting on outcome according to feeding type were included in the meta-analysis. Fixed-effects models were used and random-effects models were used when significant heterogeneity was found. The results were expressed as risk ratio (RR) with 95% confidence interval (CI). Twenty-five studies were included in the meta-analysis. Overall, probiotic supplementation resulted in a significantly lower incidence of LOS (RR 0.79 (95% CI 0.71\u20130.88), p &lt; 0.0001). According to feeding type, the beneficial effect of probiotics was confirmed only in exclusively HM-fed preterm infants (RR 0.75 (95% CI 0.65\u20130.86), p &lt; 0.0001). Among HM-fed infants, only probiotic mixtures, and not single-strain products, were effective in reducing LOS incidence (RR 0.68 (95% CI 0.57\u20130.80) p &lt; 0.00001). The results of the present meta-analysis show that probiotics reduce LOS incidence in exclusively HM-fed preterm infants. Further efforts are required to clarify the relationship between probiotics supplementation, HM, and feeding practices in preterm infants

Complementary feeding in preterm infants: a position paper by Italian neonatal, paediatric and paediatric gastroenterology joint societies

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