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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.

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.

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.

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.

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.

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' 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.

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.

This study evaluated the effect of a partly fermented infant formula (using the bacterial strains Bifidobacterium breve C50 and Streptococcus thermophilus 065) with a specific prebiotic mixture (short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS; 9:1)) on the incidence of gastrointestinal symptoms, stool characteristics, sleeping and crying behaviour, growth adequacy and safety. Two-hundred infants ≤28 days of age were assigned either to experimental infant formula containing 30% fermented formula and 0.8 g/100 mL scGOS/lcFOS or to non-fermented control infant formula without scGOS/lcFOS. A group of breastfed infants served as a reference. No relevant differences in parent-reported gastrointestinal symptoms were observed. Stool consistency was softer in the experimental versus control group with values closer to the breastfed reference group. Daily weight gain was equivalent for both formula groups (0.5 SD margins) with growth outcomes close to breastfed infants. No clinically relevant differences in adverse events were observed, apart from a lower investigator-reported prevalence of infantile colic in the experimental versus control group (1.1% vs. 8.7%; p < 0.02). Both study formulae are well-tolerated, support an adequate infant growth and are safe for use in healthy term infants. Compared to the control formula, the partly fermented formula with prebiotics induces stool consistencies closer to breastfed 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.

Functional regurgitation (FR) is common in early infancy and represents a major drain on healthcare resources. This double-blind, randomized controlled trial investigated the effects of a formula containing partially hydrolysed, 100% whey protein, starch and Lactobacillus reuteri (DSM 17938) on gastric emptying rate (GErate) and regurgitation frequency in infants with FR. Enrolled infants were randomly allocated to receive either the test formula or a standard starter formula for four weeks. Ultrasound GErate assessment was performed at baseline (week 0) and at week 4; the number of regurgitations, feed volumes and potential adverse events were recorded in a daily diary. Eighty infants aged four weeks to five months were enrolled; 72 (test group = 37; control group = 35) completed the study. Compared to controls, the test group showed greater percentage changes in GErate (12.3% vs. 9.1%, p < 0.01). Mean daily regurgitations decreased from 7.4 (0.8) at week 0 to 2.6 (1.0) at week 4 in the test group and from 7.5 (1.0) to 5.3 (1.0) in controls (between-group difference, p < 0.0001). Compared to a standard formula, a starch-thickened partially hydrolysed whey protein formula supplemented with Lactobacillus reuteri is more effective in decreasing the frequency of regurgitation and improving GErate, and can be of benefit to infants with FR., Competing Interests: Infant formula for the study was supplied by the Nestlé company. The Nestlé Company provided no other funding for the study and had no role in the design of the study. FI serve as a speaker for NNI. The authors declare that they have received no individual funding from Nestlé company, including conference attendance in the past five years.

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' 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 0.71-0.88), 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 0.65-0.86), 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 0.57-0.80) 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., Competing Interests: The authors declare no conflict of interest.

Probiotics have been linked to a reduction in the incidence of necrotizing enterocolitis and late-onset sepsis in preterm infants. Recently, probiotics have also proved to reduce time to achieve full enteral feeding (FEF). However, the relationship between FEF achievement and type of feeding in infants treated with probiotics has not been explored yet. The aim of this systematic review and meta-analysis was to evaluate the effect of probiotics in reducing time to achieve FEF in preterm infants, according to type of feeding (exclusive human milk (HM) vs. formula). Randomized-controlled trials involving preterm infants receiving probiotics, and reporting on time to reach FEF were included in the systematic review. Trials reporting on outcome according to type of feeding (exclusive HM vs. formula) were included in the meta-analysis. Fixed-effect or random-effects models were used as appropriate. Results were expressed as mean difference (MD) with 95% confidence interval (CI). Twenty-five studies were included in the systematic review. In the five studies recruiting exclusively HM-fed preterm infants, those treated with probiotics reached FEF approximately 3 days before controls (MD -3.15 days (95% CI -5.25/-1.05), p = 0.003). None of the two studies reporting on exclusively formula-fed infants showed any difference between infants receiving probiotics and controls in terms of FEF achievement. The limited number of included studies did not allow testing for other subgroup differences between HM and formula-fed infants. However, if confirmed in further studies, the 3-days reduction in time to achieve FEF in exclusively HM-fed preterm infants might have significant implications for their clinical management.