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

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 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 < 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 < 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 < 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

Microbial Community Dynamics in Mother’s Milk and Infant’s Mouth and Gut in Moderately Preterm Infants

Mother’s own milk represents the optimal source for preterm infant nutrition, as it promotes immune defenses and gastrointestinal function, protects against necrotizing enterocolitis, improves long-term clinical outcome and is hypothesized to drive gut microbiota assembly. Preterm infants at birth usually do not receive their mother’s milk directly from the breast, because active suckling and coordination between suckling, swallowing and breathing do not develop until 32–34 weeks gestational age, but actual breastfeeding is usually possible as they grow older. Here, we enrolled moderately preterm infants (gestational age 32–34 weeks) to longitudinally characterize mothers’ milk and infants’ gut and oral microbiomes, up to more than 200 days after birth, through 16S rRNA sequencing. This peculiar population offers the chance to disentangle the differential contribution of human milk feeding per se vs. actual breastfeeding in the development of infant microbiomes, that have both been acknowledged as crucial contributors to short and long-term infant health status. In this cohort, the milk microbiome composition seemed to change following the infant’s latching to the mother’s breast, shifting toward a more diverse microbial community dominated by typical oral microbes, i.e., Streptococcus and Rothia. Even if all infants in the present study were fed human milk, features typical of healthy, full term, exclusively breastfed infants, i.e., high percentages of Bifidobacterium and low abundances of Pseudomonas in fecal and oral samples, respectively, were detected in samples taken after actual breastfeeding started. These findings underline the importance of encouraging not only human milk feeding, but also an early start of actual breastfeeding in preterm infants, since the infant’s latching to the mother’s breast might constitute an independent factor helping the health-promoting assembly of the infant gut microbiome

Human Milk’s Hidden Gift: Implications of the Milk Microbiome for Preterm Infants’ Health

Breastfeeding is considered the gold standard for infants’ nutrition, as mother’s own milk (MOM) provides nutritional and bioactive factors functional to optimal development. Early life microbiome is one of the main contributors to short and long-term infant health status, with the gut microbiota (GM) being the most studied ecosystem. Some human milk (HM) bioactive factors, such as HM prebiotic carbohydrates that select for beneficial bacteria, and the specific human milk microbiota (HMM) are emerging as early mediators in the relationship between the development of GM in early life and clinical outcomes. The beneficial role of HM becomes even more crucial for preterm infants, who are exposed to significant risks of severe infection in early life as well as to adverse short and long-term outcomes. When MOM is unavailable or insufficient, donor human milk (DHM) constitutes the optimal nutritional choice. However, little is known about the specific effect of DHM on preterm GM and its potential functional implication on HMM. The purpose of this narrative review is to summarize recent findings on HMM origin and composition and discuss the role of HMM on infant health and development, with a specific focus on preterm infants

Oxidative Stress and Necrotizing Enterocolitis: Pathogenetic Mechanisms, Opportunities for Intervention, and Role of Human Milk

This review will examine the role of oxidative stress (OS) in the pathogenesis of necrotizing enterocolitis (NEC) and explore potential preventive and therapeutic antioxidant strategies. Preterm infants are particularly exposed to OS as a result of several perinatal stimuli and constitutive defective antioxidant defenses. For this reason, OS damage represents a contributing factor to several complications of prematurity, including necrotizing enterocolitis (NEC). Being NEC a multifactorial disease, OS may act as downstream component of the pathogenetic cascade. To counteract OS in preterm infants with NEC, several antioxidant strategies have been proposed and different antioxidant compounds have been experimented. It is well known that human milk (HM) is an important source of antioxidants. At the same time, the role of an exclusive HM diet is well recognized in the prevention of NEC. However, donor HM (DHM) processing may impair antioxidant properties. As DHM is becoming a common nutritional intervention for high risk PI, the antioxidant status of preterm and DHM and potential ways to preserve its antioxidant capacity may merit further investigation

Filling the Gaps: Current Research Directions for a Rational Use of Probiotics in Preterm Infants

The use of probiotics among very low-birth-weight infants is constantly increasing, as probiotics are believed to reduce the incidence of severe diseases such as necrotizing enterocolitis and late-onset sepsis and to improve feeding tolerance. However, despite the enthusiasm towards these products in neonatal medicine, theoretical knowledge and clinical applications still need to be improved. The purpose of this review is to give an overview of the most important gaps in the current literature about potential uses of probiotics in preterm infants, highlighting promising directions for future research. Specifically, further well-designed studies should aim at clarifying the impact of the type of feeding (mother’s milk, donor milk, and formula) on the relationship between probiotic supplementation and clinical outcome. Moreover, future research is needed to provide solid evidence about the potential greater efficacy of multi-strain probiotics compared to single-strain products. Safety issues should also be addressed properly, by exploring the potential of paraprobiotics and risks connected to antibiotic resistance in preterm infants. Last, in light of increasing commercial and public interests, the long-term effect of routine consumption of probiotics in such a vulnerable population should be also evaluated

To Feed or Not to Feed: A Critical Overview of Enteral Feeding Management and Gastrointestinal Complications in Preterm Neonates with a Patent Ductus Arteriosus

The management of enteral feeds in preterm infants with a hemodynamically significant patent ductus arteriosus (hs-PDA) is a major challenge for neonatologists due to the fear of gastrointestinal (GI) complications. This review aims to analyze the available evidence on the complex relation between the presence and management of PDA, enteral feeding practices, and GI outcomes in the preterm population. There is limited evidence, based on small and heterogeneous trials, that hs-PDA may affect the splanchnic hemodynamic response to enteral feeds. While the presence of PDA seems a risk factor for adverse GI outcomes, the benefits of feeding withholding during pharmacological PDA treatment are controversial. The lack of robust evidence in support of or against a timely feeding introduction or feeding withholding during pharmacological PDA closure in preterm neonates does not allow to draw any related recommendation. While waiting for further data, the feeding management of this population should be carefully evaluated and possibly individualized on the basis of the infants\u2019 hemodynamic and clinical characteristics. Large, multicentric trials would help to better clarify the physiological mechanisms underlying the development of gut hypoperfusion, and to evaluate the impact of enteral feeds on splanchnic hemodynamics in relation to PDA features and treatment

Biotics in neonatal period: what's the evidence?

Breastfeeding is considered the gold standard for infants' nutrition and provides unique benefits for infants' health