Bifidobacterium infantis has special abilities to utilise human milk oligosaccharides. Hence we hypothesised that probiotic supplements containing B. infantis may confer greater benefits to preterm infants than probiotic supplements without B. infantis.

A systematic review with meta-analysis was conducted according to standard guidelines. We selected RCTs evaluating probiotics compared to placebo or no treatment in preterm and/or low birth weight infants. Probiotic effects on Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS) and Mortality were analysed separately for RCTs in which the supplemented probiotic product contained B. infantis and those that did not contain B. infantis.

67 RCTs were included (n = 14,606), of which 16 used probiotics containing B. infantis (Subgroup A) and 51 RCTs did not (Subgroup B) Meta-analysis of all RCTs indicated that probiotics reduced the risk of NEC, LOS, and mortality. The subgroup meta-analysis demonstrated greater reduction in the incidence of NEC in subgroup A than subgroup B [(relative risk in subgroup A: 0.38; 95% CI, 0.27-0.55) versus (0.67; 95% CI, 0.55-0.81) in subgroup B; p value for subgroup difference: 0.01].

These results provide indirect evidence that probiotic supplements that include B. infantis may be more beneficial for preterm infants. Well-designed RCTs are necessary to confirm these findings.

Evidence is emerging that beneficial effects of probiotics are species and strain specific. This systematic review analyses if B. infantis supplementation provides an advantage to preterm infants. This is the first systematic review evaluating the effects of probiotics containing B. infantis in preterm infants. The results of this systematic review provides indirect evidence that probiotics that include B. infantis may be more beneficial for preterm infants. These results will help in guiding future research and clinical practice for using B. infantis as a probiotic in preterm infants.

Probiotics are known to decrease incidences of necrotising enterocolitis, feeding intolerance, late-onset sepsis, and mortality in preterm infants. Administering an adequate dose is important for optimizing the benefits and safety of probiotics. We conducted a systematic review to assess the effect of probiotic dose escalation on clinical outcomes and gut microbiota in preterm neonates. We searched PubMed, EMBASE, EMCARE, Medline, Cochrane Library, Google Scholar, and MedNar databases in July 2023. Three studies were included. In one of the randomized studies (n = 149, gestation 27 to 33 weeks), no significant differences in faecal Lactobacillus and Bifidobacterium counts and clinical outcomes were seen between the high- and low-dose groups. There was a trend towards increased Lactobacillus and Bifidobacterium counts in the high-dose group. In the other randomized study (n = 120, birth weight 500 to 2000 gm), smaller infants (500 to 1000 gm) required higher doses to display Lactobacillus in their faeces. The cohort study (n = 12, gestation < 33 weeks) showed a trend towards an increase in faecal abundance of bifidobacteria and bacterial diversity in the B. infantis group with increasing dose/time. Limited evidence suggests a higher dose might improve gut colonization in preterm infants. Further studies are urgently needed to address this gap in the knowledge considering the increasing use of probiotics for preterm infants.

The present study aimed to review probiotics' clinical efficacy in preventing infectious diseases among hospitalized patients in ICU and non-ICU wards.

A search of Medline, EMBASE, The Cochrane Library, Science Direct, Open Grey, and Google Scholar was conducted for eligible publications from 2002 to 2020 following the requirements outlined in the PRISMA guideline. The search strategy was based on the combination of the following terms: "probiotics," "prebiotics," "synbiotics," and "cross-infection." The logical operators "AND" (or the equivalent operator for the databases) and "OR" (e.g., probiotics OR prebiotics OR synbiotics) were used.

The results indicated that the probiotic consumption caused a significant reduction in antibiotic-associated diarrhea (AAD) and Clostridioides difficile infection (CDI) in 2/8 randomized clinical trials (RCTs) investigating AAD/CDI. Also, 5/12 clinical trials highlighted the considerable effects of probiotics on the reduction or prevention of ventilator associated pneumoniae (VAP), so the mean prevalence of VAP was lower in the probiotic group than in the placebo group. The total rate of nosocomial infections among preterm infants was nonsignificantly higher in the probiotic group compared to the control group.

This systematic review shows that the administration of probiotics has moderate preventive or mitigating effects on the occurrence of VAP in ICU patients, CDI, AAD, and nosocomial infections among children. Consequently, applying antibiotics along with the proper probiotic species can be advantageous.

Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity in very preterm or VLBW infants.

To determine the effect of supplemental probiotics on the risk of NEC and associated mortality and morbidity in very preterm or very low birth weight infants.

We searched CENTRAL, MEDLINE, Embase, the Maternity and Infant Care database, and CINAHL from inception to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles.

We included randomised controlled trials (RCTs) and quasi-RCTs comparing probiotics with placebo or no probiotics in very preterm infants (born before 32 weeks' gestation) and VLBW infants (weighing less than 1500 g at birth).

Two review authors independently evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with associated 95% confidence intervals (CIs). The primary outcomes were NEC and all-cause mortality; secondary outcome measures were late-onset invasive infection (more than 48 hours after birth), duration of hospitalisation from birth, and neurodevelopmental impairment. We used the GRADE approach to assess the certainty of the evidence.

We included 60 trials with 11,156 infants. Most trials were small (median sample size 145 infants). The main potential sources of bias were unclear reporting of methods for concealing allocation and masking caregivers or investigators in about half of the trials. The formulation of the probiotics varied across trials. The most common preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., andStreptococcus spp., alone or in combination. Very preterm or very low birth weight infants Probiotics may reduce the risk of NEC (RR 0.54, 95% CI 0.46 to 0.65; I² = 17%; 57 trials, 10,918 infants; low certainty). The number needed to treat for an additional beneficial outcome (NNTB) was 33 (95% CI 25 to 50). Probiotics probably reduce mortality slightly (RR 0.77, 95% CI 0.66 to 0.90; I² = 0%; 54 trials, 10,484 infants; moderate certainty); the NNTB was 50 (95% CI 50 to 100). Probiotics probably have little or no effect on the risk of late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; I² = 22%; 49 trials, 9876 infants; moderate certainty). Probiotics may have little or no effect on neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26; I² = 0%; 5 trials, 1518 infants; low certainty). Extremely preterm or extremely low birth weight infants Few data were available for extremely preterm or extremely low birth weight (ELBW) infants. In this population, probiotics may have little or no effect on NEC (RR 0.92, 95% CI 0.69 to 1.22, I² = 0%; 10 trials, 1836 infants; low certainty), all-cause mortality (RR 0.92, 95% CI 0.72 to 1.18; I² = 0%; 7 trials, 1723 infants; low certainty), or late-onset invasive infection (RR 0.93, 95% CI 0.78 to 1.09; I² = 0%; 7 trials, 1533 infants; low certainty). No trials provided data for measures of neurodevelopmental impairment in extremely preterm or ELBW infants.

Given the low to moderate certainty of evidence for the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or VLBW infants, and particularly for extremely preterm or ELBW infants, there is a need for further large, high-quality trials to provide evidence of sufficient validity and applicability to inform policy and practice.

Necrotizing enterocolitis (NEC) is an infectious and inflammatory intestinal disease that is the most common surgical emergency in the premature patient population. Although the etiology of the disease is multifactorial, intestinal dysbiosis is a hallmark of this disease. Based on this, probiotics may play a therapeutic role in NEC by introducing beneficial bacteria with immunomodulating, antimicrobial, and anti-inflammatory functions into the gastrointestinal tract. Currently, there is no Food and Drug Administration (FDA)-approved probiotic for the prevention and treatment of NEC. All probiotic clinical studies to date have administered the bacteria in their planktonic (free-living) state. This review will discuss established probiotic delivery systems including planktonic probiotics, prebiotics, and synbiotics, as well as novel probiotic delivery systems such as biofilm-based and designer probiotics. We will also shed light on whether or not probiotic efficacy is influenced by administration with breast milk. Finally, we will consider the challenges associated with developing an FDA-approved probiotic for NEC.

The starting time for probiotic supplementation in preterm infants after birth varies widely. This study aimed to investigate the optimal time for initiating probiotics to reduce adverse outcomes in preterm or very low birth weight (VLBW) infants.

Medical records of preterm infants born at a gestational age (GA) of <32 weeks or VLBW infants in 2011-2020 were reviewed respectively. The infants who received Saccharomyces boulardii probiotics within 7 days of birth were grouped into an early introduction (EI) group, and those who received supplemented probiotics after 7 days of birth were part of the late introduction (LI) group. Clinical characteristics were compared between the two groups and analyzed statistically.

A total of 370 infants were included. The mean GA (29.1 weeks vs. 31.2 weeks, p<0.001) and birth weight (1,235.9 g vs. 1491.4 g, p<0.001) were lower in the LI group (n=223) than in the EI group. The multivariate analysis indicated that factors affecting the LI of probiotics were GA at birth (odds ratio [OR], 1.52; p<0.001) and the enteral nutrition start day (OR, 1.47; p<0.001). The late probiotic introduction was associated with a risk of late-onset sepsis (OR, 2.85; p=0.020), delayed full enteral nutrition (OR, 5.44; p<0.001), and extrauterine growth restriction (OR, 1.67; p=0.033) on multivariate analyses after adjusting for GA.

Early supplementation of probiotics within a week after birth may reduce adverse outcomes among preterm or VLBW infants.

Necrotizing enterocolitis (NEC) is a complex intestinal disease that primarily affects premature neonates. Given its significant mortality and morbidity, there is an urgent need to develop improved prophylactic measures against the disease. One potential preventative strategy for NEC is the use of probiotics. Although there has been significant interest for decades in probiotics in neonatal care, no clear guidelines exist regarding which probiotic to use or for which patients, and no FDA-approved products exist on the market for NEC. In addition, there is lack of agreement regarding the benefits of probiotics in neonates, as well as some concerns about the safety and efficacy of available products. We discuss currently available probiotics as well as next-generation probiotics and novel delivery strategies which may offer an avenue to capitalize on the benefits of probiotics, while minimizing the risks. Thus, probiotics may still prove to be an effective prevention strategy for NEC, although further product development and research is needed to support use in the preterm population.

Probiotics are gradually being used as a supplementation to prevent necrotizing enterocolitis (NEC) and reduce mortality in neonates. We performed an updated meta-analysis to systematically evaluate the efficacy and safety of prophylactic probiotic supplementation for preventing NEC.

The databases including PubMed, Embase, Scopus, Web of Science, and China National Knowledge Infrastructure were used to search the relevant articles. The latest retrieval date was up to December 2021. The meta-analysis was performed using Stata version 10.0. Finally, a total of 70 studies containing 8319 cases and 9283 controls were included. The strength of the association between the supplementation of probiotics and NEC was measured by risk ratios (RRs) with 95% confidence intervals (CIs). Pooled effect sizes across studies were performed by a random effect model.

The results showed that the probiotics could significantly reduce the incidence of NEC (stage II or more) (RR = 0.436, 95% CI = 0.357-0.531, P < .001), the overall mortality (RR = 0.651, 95% CI = 0.506-0.836, P < .001), and NEC-related mortality (RR = 0.639, 95% CI = 0.423-0.966, P = .034). Due to the lack of sufficient sample size, we did not perform the subgroup analysis by types of probiotic strain.

This meta-analysis indicates that the use of probiotics can effectively reduce the occurrence of NEC and mortality in neonates.

The development and health of infants are intertwined with the protective and regulatory functions of different microorganisms in the gut known as the gut microbiota. Preterm infants born with an imbalanced gut microbiota are at substantial risk of several diseases including inflammatory intestinal diseases, necrotizing enterocolitis, late-onset sepsis, neurodevelopmental disorders, and allergies which can potentially persist throughout adulthood. In this review, we have evaluated the role of Bifidobacterium as commonly used probiotics in the development of gut microbiota and prevention of common diseases in preterm infants which is not fully understood yet. The application of Bifidobacterium as a therapeutical approach in the re-programming of the gut microbiota in preterm infants, the mechanisms of host-microbiome interaction, and the mechanism of action of this bacterium have also been investigated, aiming to provide new insights and opportunities in microbiome-targeted interventions in personalized medicine.

Necrotizing enterocolitis (NEC) is a common gastrointestinal disease of preterm infants with high morbidity and mortality. In survivors of NEC, one of the leading causes of long-term morbidity is the development of severe neurocognitive injury. The exact pathogenesis of neurodevelopmental delay in NEC remains unknown, but microbiota is considered to have dramatic effects on the development and function of the host brain via the gut-brain axis. In this review, we discuss the characteristics of microbiota of NEC, the impaired neurological outcomes, and the role of the complex interplay between the intestinal microbiota and brain to influence neurodevelopment in NEC. The increasing knowledge of microbial-host interactions has the potential to generate novel therapies for manipulating brain development in the future.

Microbiome-targeting therapies have received great attention as approaches to prevent disease in infants born preterm, but their safety and efficacy remain uncertain. Here we summarize the existing literature, focusing on recent meta-analyses and systematic reviews that evaluate the performance of probiotics, prebiotics, and/or synbiotics in clinical trials and studies, emphasizing interventions for which the primary or secondary outcomes were prevention of necrotizing enterocolitis, late-onset sepsis, feeding intolerance, and/or reduction in hospitalization length or all-cause mortality. Current evidence suggests that probiotics and prebiotics are largely safe but conclusions regarding their effectiveness in the neonatal intensive care unit have been mixed. To address this ambiguity, we evaluated publications that collectively support benefits of probiotics with moderate to high certainty evidence in a recent comprehensive network meta-analysis, highlighting limitations in these trials that make it difficult to support with confidence the routine, universal administration of probiotics to preterm infants.

This study aims to review the evidence for the optimal regimen of probiotics for the prevention of necrotizing enterocolitis (NEC) in very low birth weight infants.

Through searching PubMed, EMBASE, Cochrane Library, and Web of Science till September 30, 2022, only randomized controlled trials were included to evaluate the optimal regimen of probiotics for the prevention of NEC in very low birth weight infants. The methodological quality of the included studies was assessed by the Cochrane risk of bias assessment tool (RoB 2), and the collected data were analyzed accordingly using Stata software.

Twenty-seven RCTs were included, and the total sample size used in the study was 529. The results of the network meta-analysis showed that Bovine lactoferrin + Lactobacillus rhamnosus GG (RR 0.03; 95% CI 0.00-0.35), Lactobacillus rhamnosus + Lactobacillus plantarum + Lactobacillus casei + Bifidobacterium lactis (RR 0.06; 95% CI 0.00-0.70), Bifidobacterium lactis + inulin (RR 0.16; 95% CI 0.03-0.91) were superior to the control group (Bifidobacterium lactis + Bifidobacterium longum) in reducing the incidence of NEC. The reduction in the incidence of NEC were as follows: Bovine lactoferrin + Lactobacillus rhamnosus GG (SUCRA 95.7%) > Lactobacillus rhamnosus + Lactobacillus plantarum + Lactobacillus casei + Bifidobacterium lactis (SUCRA 89.4%) > Bifidobacterium lactis + inulin (SUCRA 77.8%).

This network meta-analysis suggests that Lactobacillus rhamnosus GG combined with bovine lactoferrin maybe the most recommended regimen for the prevention of NEC in very low birth weight infants.

Bifidobacteria are among the predominant microorganisms during infancy, being a dominant microbial group in the healthy breastfed infant and playing a crucial role in newborns and infant development. Not only the levels of the Bifidobacterium genus but also the profile and quantity of the different bifidobacterial species have been demonstrated to be of relevance to infant health. Although no definitive proof is available on the causal association, reduced levels of bifidobacteria are perhaps the most frequently observed alteration of the intestinal microbiota in infant diseases. Moreover, Bifidobacterium strains have been extensively studied by their probiotic attributes. This review compiles the available information about bifidobacterial composition and function since the beginning of life, describing different perinatal factors affecting them, and their implications on different health alterations in infancy. In addition, this review gathers exhaustive information about pre-clinical and clinical studies with Bifidobacterium strains as probiotics in neonates.

To assess the eligibility criteria and trial characteristics among contemporary (2010-2019) randomized clinical trials (RCTs) that included infants born extremely preterm (<28 weeks of gestation) and to evaluate whether eligibility criteria result in underrepresentation of high-risk subgroups (eg, infants born at <24 weeks of gestation).

PubMed and Scopus were searched January 1, 2010, to December 31, 2019, with no language restrictions. RCTs with mean or median gestational ages at birth of <28 weeks of gestation were included. The study followed the PRISMA guidelines; outcomes were registered prospectively. Data extraction was performed independently by multiple observers. Study quality was evaluated using a modified Jadad scale.

Among RCTs (n = 201), 32 552 infants were included. Study participant characteristics, interventions, and outcomes were highly variable. A total of 1603 eligibility criteria were identified; rationales were provided for 18.8% (n = 301) of criteria. Fifty-five RCTs (27.4%) included infants <24 weeks of gestation; 454 (1.4%) infants were identified as <24 weeks of gestation.

The present study identifies sources of variability across RCTs that included infants born extremely preterm and reinforces the critical need for consistent and transparent policies governing eligibility criteria.

To study the efficacy of probiotics in preventing late-onset sepsis (LOS) in very low birth weight (VLBW) infants.

Databases including PubMed, Web of Science, Cochrane Library, Wanfang Data, China National Knowledge Infrastructure, and Chinese Biomedical Literature Database were searched for randomized controlled trials (RCTs) of probiotics in preventing LOS in VLBW infants. LOS was classified as clinical LOS and confirmed LOS. RevMan 5.4 was used to perform the Meta analysis.

A total of 31 RCTs were included, with 3 490 VLBW infants in the probiotics group and 3 376 VLBW infants in the control group. The Meta analysis showed that compared with the control group, the probiotics group had significantly lower risks of clinical LOS (RR=0.79, 95%CI:0.66-0.94, P=0.009) and clinical/confirmed LOS (RR=0.79, 95% CI:0.67-0.94, P=0.007). In the probiotics group, the infants receiving exclusive breastfeeding had a significantly lower risk of confirmed LOS (RR=0.77, 95%CI:0.62-0.96, P=0.02).

Current evidence indicates that probiotics may reduce the risk of clinical LOS and clinical/confirmed LOS in VLBW infants, and the risk of confirmed LOS in VLBW infants who are exclusively breastfed.

The diversity of probiotic products makes choosing an appropriate probiotic challenging. One unanswered question is whether single-strain probiotics are more effective than multi-strain mixtures. The aim of this review is to account for both disease and strain specificity to determine whether single strains or multiple strains are equivalent or more effective. This literature review of randomized controlled trials from 1973 to 2019 was used to compare the pooled efficacy of trials with a single strain versus the probiotic mixture with same matched strain within the same type of disease indication. A total of 65 RCTs were included (41 with single strains, 22 multi-strain mixtures and 2 comparing single strain to mixture arms) for eight different disease indications (N = 10,863). Only three strains (L. rhamnosus GG, L. helveticus R52 and B. lactis Bb12) had corresponding trials with matching mixtures. Use of L. rhamnosus GG only was significantly more protective for necrotizing enterocolitis compared to two mixtures also containing different strains of B. lactis. The mixture of L. rhamnosus GG and B. lactis Bb12 was significantly more effective than L. rhamnosus GG alone for the eradication of H. pylori. In most cases, single strains were equivalent to mixtures. Choice of an appropriate probiotic should be based, not on the number of strains in the product, rather based on evidence-based trials of efficacy. In most cases, multi-strain mixtures were not significantly more effective than single-strain probiotics.

The last two decades have seen a significant decrease in mortality for children <5 years of age in low and middle-income countries (LMICs); however, neonatal (age, 0-28 days) mortality has not decreased at the same rate. We assessed three neonatal nutritional interventions that have the potential of reducing morbidity and mortality during infancy in LMICs.

To determine the efficacy and effectiveness of synthetic vitamin A, dextrose oral gel, and probiotic supplementation during the neonatal period.

We conducted electronic searches for relevant studies on the following databases: PubMed, CINAHL, LILACS, SCOPUS, and CENTRAL, Cochrane Central Register for Controlled Trials, up to November 27, 2019.

We aimed to include randomized and quasi-experimental studies. The target population was neonates in LMICs. The interventions included synthetic vitamin A supplementation, oral dextrose gel supplementation, and probiotic supplementation during the neonatal period. We included studies from the community and hospital settings irrespective of the gestational age or birth weight of the neonate.

Two authors screened the titles and extracted the data from selected studies. The risk of bias (ROB) in the included studies was assessed according to the Cochrane Handbook of Systematic Reviews. The primary outcome was all-cause mortality. The secondary outcomes were neonatal sepsis, necrotizing enterocolitis (NEC), prevention and treatment of neonatal hypoglycaemia, adverse events, and neurodevelopmental outcomes. Data were meta-analyzed by random effect models to obtain relative risk (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean difference with 95% CI for continuous outcomes. The overall rating of evidence was determined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Sixteen randomized studies (total participants 169,366) assessed the effect of vitamin A supplementation during the neonatal period. All studies were conducted in low- and middle-income (LMIC) countries. Thirteen studies were conducted in the community setting and three studies were conducted in the hospital setting, specifically in neonatal intensive care units. Studies were conducted in 10 different countries including India (four studies), Guinea-Bissau (three studies), Bangladesh (two studies), and one study each in China, Ghana, Indonesia, Nepal, Pakistan, Tanzania, and Zimbabwe. The overall ROB was low in most of the included studies for neonatal vitamin A supplementation. The pooled results from the community based randomized studies showed that there was no significant difference in all-cause mortality in the vitamin A (intervention) group compared to controls at 1 month (RR, 0.99; 95% CI, 0.90-1.08; six studies with 126,548 participants, statistical heterogeneity I 2 0%, funnel plot symmetrical, grade rating high), 6 months (RR, 0.98; 95% CI, 0.89-1.07; 12 studies with 154,940 participants, statistical heterogeneity I 2 43%, funnel plot symmetrical, GRADE quality high) and 12 months of age (RR, 1.04; 95% CI, 0.94-1.14; eight studies with 118,376 participants, statistical heterogeneity I 2 46%, funnel plot symmetrical, GRADE quality high). Neonatal vitamin A supplementation increased the incidence of bulging fontanelle by 53% compared to control (RR, 1.53; 95% CI, 1.12-2.09; six studies with 100,256 participants, statistical heterogeneity I 2 65%, funnel plot symmetrical, GRADE quality high). We did not identify any experimental study that addressed the use of dextrose gel for the prevention and/or treatment of neonatal hypoglycaemia in LMIC. Thirty-three studies assessed the effect of probiotic supplementation during the neonatal period (total participants 11,595; probiotics: 5854 and controls: 5741). All of the included studies were conducted in LMIC and were randomized. Most of the studies were done in the hospital setting and included participants who were preterm (born < 37 weeks gestation) and/or low birth weight (<2500 g birth weight). Studies were conducted in 13 different countries with 10 studies conducted in India, six studies in Turkey, three studies each in China and Iran, two each in Mexico and South Africa, and one each in Bangladesh, Brazil, Colombia, Indonesia, Nepal, Pakistan, and Thailand. Three studies were at high ROB due to lack of appropriate randomization sequence or allocation concealment. Combined data from 25 studies showed that probiotic supplementation reduced all-cause mortality by 20% compared to controls (RR, 0.80; 95% CI, 0.66-0.96; total number of participants 10,998, number needed to treat 100, statistical heterogeneity I 2 0%, funnel plot symmetrical, GRADE quality high). Twenty-nine studies reported the effect of probiotics on the incidence of NEC, and the combined results showed a relative reduction of 54% in the intervention group compared to controls (RR, 0.46; 95% CI, 0.35-0.59; total number of participants 5574, number needed to treat 17, statistical heterogeneity I 2 24%, funnel plot symmetrical, GRADE quality high). Twenty-one studies assessed the effect of probiotic supplementation during the neonatal period on neonatal sepsis, and the combined results showed a relative reduction of 22% in the intervention group compared to controls (RR, 0.78; 95% CI, 0.70-0.86; total number of participants 9105, number needed to treat 14, statistical heterogeneity I 2 23%, funnel plot symmetrical, GRADE quality high).

Vitamin A supplementation during the neonatal period does not reduce all-cause neonatal or infant mortality in LMICs in the community setting. However, neonatal vitamin A supplementation increases the risk of Bulging Fontanelle. No experimental or quasi-experimental studies were available from LMICs to assess the effect of dextrose gel supplementation for the prevention or treatment of neonatal hypoglycaemia. Probiotic supplementation during the neonatal period seems to reduce all-cause mortality, NEC, and sepsis in babies born with low birth weight and/or preterm in the hospital setting. There was clinical heterogeneity in the use of probiotics, and we could not recommend any single strain of probiotics for wider use based on these results. There was a lack of studies on probiotic supplementation in the community setting. More research is needed to assess the effect of probiotics administered to neonates in-home/community setting in LMICs.

Recent evidence supports a role of probiotics in preventing necrotizing enterocolitis (NEC) in preterm infants.

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.

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).

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.

Probiotics have proven to be effective in promoting premature infants' health, but the optimal usage is unknown.

To compare probiotic supplements for premature infants.

We searched PubMed, Embase, Cochrane, and ProQuest from inception of these databases to June 1, 2020.

Randomized trials of probiotic supplement intervention for preterm infants were screened by 2 reviewers independently. The primary outcomes were mortality and the morbidity of necrotizing enterocolitis (NEC). Secondary outcomes were morbidity of sepsis, time to achieve full enteral feeding, and length of hospital stay.

The data of primary and secondary outcomes were extracted by 2 reviewers and pooled with a random-effects model.

The meta-analysis included 45 trials with 12 320 participants. Bifidobacterium plus Lactobacillus was associated with lower rates of mortality (risk ratio 0.56; 95% credible interval 0.34-0.84) and NEC morbidity (0.47; 0.27-0.79) in comparison to the placebo; Lactobacillus plus prebiotic was associated with lower rates of NEC morbidity (0.06; 0.01-0.41) in comparison to the placebo; Bifidobacterium plus prebiotic had the highest probability of having the lowest rate of mortality (surface under the cumulative ranking curve 83.94%); and Lactobacillus plus prebiotic had the highest probability of having the lowest rate of NEC (surface under the cumulative ranking curve 95.62%).

In few studies did authors report the data of infants with a lower birth weight or gestational age.

The efficacy of single probiotic supplements is limited, compared to combined use of probiotics. To achieve optimal effect on premature infant health, combined use of prebiotic and probiotic, especially Lactobacillus or Bifidobacterium, is recommended.

Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity.  OBJECTIVES: To determine the effect of supplemental probiotics on the risk of NEC and mortality and morbidity in very preterm or very low birth weight infants.

We searched Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 2) in the Cochrane Library; MEDLINE Ovid (1946 to 17 Feb 2020), Embase Ovid (1974 to 17 Feb 2020), Maternity & Infant Care Database Ovid (1971 to 17 Feb 2020), the Cumulative Index to Nursing and Allied Health Literature (1982 to 18 Feb 2020). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs.

We included RCTs and quasi-RCTs comparing probiotic supplementation with placebo or no probiotics in very preterm or very low birth weight infants.

We used the standard methods of Cochrane Neonatal. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on NEC, all-cause mortality, late-onset infection, and severe neurodevelopmental impairment.

We included 56 trials in which 10,812 infants participated. Most trials were small (median sample size 149). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were the main potential sources of bias in about half of the trials. Trials varied by the formulation of the probiotics. The most commonly used preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., and Streptococcus spp. alone or in combinations. Meta-analysis showed that probiotics may reduce the risk of NEC: RR 0.54, 95% CI 0.45 to 0.65 (54 trials, 10,604 infants; I² = 17%); RD -0.03, 95% CI -0.04 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 25 to 50. Evidence was assessed as low certainty because of the limitations in trials design, and the presence of funnel plot asymmetry consistent with publication bias. Sensitivity meta-analysis of trials at low risk of bias showed a reduced risk of NEC: RR 0.70, 95% CI 0.55 to 0.89 (16 trials, 4597 infants; I² = 25%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100. Meta-analyses showed that probiotics probably reduce mortality (RR 0.76, 95% CI 0.65 to 0.89; (51 trials, 10,170 infants; I² = 0%); RD -0.02, 95% CI -0.02 to -0.01; NNTB 50, 95% CI 50 to 100), and late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; (47 trials, 9762 infants; I² = 19%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100). Evidence was assessed as moderate certainty for both these outcomes because of the limitations in trials design. Sensitivity meta-analyses of 16 trials (4597 infants) at low risk of bias did not show an effect on mortality or infection. Meta-analysis showed that probiotics may have little or no effect on severe neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26 (five trials, 1518 infants; I² = 0%). The certainty on this evidence is low because of limitations in trials design and serious imprecision of effect estimate. Few data (from seven of the trials) were available for extremely preterm or extremely low birth weight infants. Meta-analyses did not show effects on NEC, death, or infection (low-certainty evidence).

Given the low to moderate level of certainty about the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or very low birth weight infants, and particularly for extremely preterm or extremely low birth weight infants, further, large, high-quality trials are needed to provide evidence of sufficient quality and applicability to inform policy and practice.

We aimed to compare the effectiveness of single- vs multiple-strain probiotics in a network meta-analysis of randomized trials.

We searched MEDLINE, Embase, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, BIOSIS Previews, and Google Scholar through January 1, 2019, for studies of single-strain and multistrain probiotic formulations on the outcomes of preterm, low-birth-weight neonates. We used a frequentist approach for network meta-analysis and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence. Primary outcomes included all-cause mortality, severe necrotizing enterocolitis (NEC) (Bell stage II or more), and culture-proven sepsis.

We analyzed data from 63 trials involving 15,712 preterm infants. Compared with placebo, a combination of 1 or more Lactobacillus species (spp) and 1 or more Bifidobacterium spp was the only intervention with moderate- or high-quality evidence of reduced all-cause mortality (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.39-0.80). Among interventions with moderate- or high-quality evidence for efficacy compared with placebo, combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp, Bifidobacterium animalis subspecies lactis, Lactobacillus reuteri, or Lactobacillus rhamnosus significantly reduced severe NEC (OR, 0.35 [95% CI, 0.20-0.59]; OR, 0.31 [95% CI, 0.13-0.74]; OR, 0.55 [95% CI, 0.34-0.91]; and OR, 0.44 [95% CI, 0.21-0.90], respectively). There was moderate- or high-quality evidence that combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp and Saccharomyces boulardii reduced the number of days to reach full feeding (mean reduction of 3.30 days [95% CI, reduction of 5.91-0.69 days]). There was moderate- or high-quality evidence that, compared with placebo, the single-species product B animalis subsp lactis or L reuteri significantly reduced duration of hospitalization (mean reduction of 13.00 days [95% CI, reduction of 22.71-3.29 days] and mean reduction of 7.89 days [95% CI, reduction of 11.60-4.17 days], respectively).

In a systematic review and network meta-analysis of studies to determine the effects of single-strain and multistrain probiotic formulations on outcomes of preterm, low-birth-weight neonates, we found moderate to high evidence for the superiority of combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp vs single- and other multiple-strain probiotic treatments. The combinations of Bacillus spp and Enterococcus spp, and 1 or more Bifidobacterium spp and Streptococcus salivarius subsp thermophilus, might produce the largest reduction in NEC development. Further trials are needed.

More than 10,000 preterm infants have participated in randomised controlled trials on probiotics worldwide, suggesting that probiotics in general could reduce rates of necrotising enterocolitis (NEC), sepsis, and mortality. Answers to relevant clinical questions as to which strain to use, at what dosage, and how long to supplement are, however, not available. On the other hand, an increasing number of commercial products containing probiotics are available from sometimes suboptimal quality. Also, a large number of units around the world are routinely offering probiotic supplementation as the standard of care despite lacking solid evidence. Our recent network meta-analysis identified probiotic strains with greatest efficacy regarding relevant clinical outcomes for preterm neonates. Efficacy in reducing mortality and morbidity was found for only a minority of the studied strains or combinations. In the present position paper, we aim to provide advice, which specific strains might potentially be used and which strains should not be used. In addition, we aim to address safety issues of probiotic supplementation to preterm infants, who have reduced immunological capacities and occasional indwelling catheters. For example, quality reassurance of the probiotic product is essential, probiotic strains should be devoid of transferable antibiotic resistance genes, and local microbiologists should be able to routinely detect probiotic sepsis. Provided all safety issues are met, there is currently a conditional recommendation (with low certainty of evidence) to provide either Lactobacillus rhamnosus GG ATCC53103 or the combination of Bifidobacterium infantis Bb-02, Bifidobacterium lactis Bb-12, and Streptococcus thermophilus TH-4 in order to reduce NEC rates.

The therapeutic effect of Bifidobacterium and Lactobacillus on necrotizing enterocolitis (NEC) in very-low-birth-weight preterm infants was controversial, and we aimed to explore the exact impact of the two probiotics.

The PubMed, EMBASE, Web of Science and Cochrane Library were systematically searched for studies published from January 1, 2010 to February 28, 2019. Results were combined with fixed-effect model or random-effect model with specific conditions. Sensitivity analysis was conducted by the trim-and-fill method, and the Begger's and Egger's test were used to measure publication bias.

The meta-analysis included 16 original articles with 4632 very-low-birth-weight preterm infants. With respect to the intervention of Bifidobacterium, we estimated non-significant decrease in the morbidity of NEC with a risk ratio (RR) of 0.75 [95% confidence internal (CI) 0.56-1.01, P = 0.06]. Regarding the effect of Lactobacillus, there was no evidence of significant lower risk in the incidence of NEC (RR = 0.67, 95% CI 0.39-1.17, P = 0.16). The use of mixture of probiotics (Bifidobacterium and Lactobacillus) reduced the risk of NEC in the probiotics group (RR = 0.45, 95% CI 0.25-0.80, P = 0.007).

The mixture of Bifidobacterium and Lactobacillus could prevent the morbidity of NEC in very-low-birth-weight preterm infants. But Bifidobacterium or Lactobacillus alone did not show this effect.

To evaluate the safety and efficacy of Lactobacillus for preventing necrotizing enterocolitis (NEC) in preterm infants.

We searched the Cochrane Library, PubMed, EMBASE, and Web of Science databases from inception to September 2019. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated to compare outcomes. We also performed a subgroup analysis of the incidence of NEC. Moreover, a sensitivity analysis was performed to examine the stability of the results. A Begg funnel plot was generated to detect publication bias. Two reviewers assessed trial quality and extracted data independently. This work has been reported in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement and the Assessing the Methodological Quality of Systematic Reviews guidelines. Statistical analysis was performed using standard procedures in Review Manager 5.2 software.

Twenty-three randomized, placebo-controlled studies (N = 4686 participants) were included in this analysis. Comparing the Lactobacillus and control groups, a significant reduction was found in the incidence of NEC (RR 0.34, 95% CI 0.25-0.46; P < 0.00001) and death (RR 0.48, 95% CI 0.36-0.64; P < 0.00001). No significant difference in the incidence of sepsis was found between the Lactobacillus and placebo groups (RR 0.90, 95% CI 0.72-1.12; P = 0.34).

Lactobacillus is safe and can prevent necrotizing enterocolitis in preterm infants.

Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants. In order to evaluate the efficacy of probiotics in the prevention of stage II-III NEC, we performed a meta-analysis of clinical studies.

We searched in PubMed, Medline and Embase from 1 January 1990 to 16 January 2018. Heterogeneity was examined by Q-test. Publication bias was evaluated by funnel plot and Egger's regression test.

30 articles were identified meeting the inclusion criteria. Data showed that probiotics supplement could significantly reduce the risk of stage II-III NEC (RR = 0.51, 95% CI, 0.38 to 0.67, P < 0.001) and death rate (RR = 0.69, 95% CI, 0.55 to 0.87, P = 0.002). The mixed probiotics and lactobacillus could reduce the risk of stage II-III NEC (for mixed probiotics, RR = 0.39, 95% CI, 0.26 to 0.57; for lactobacillus, RR = 0.53, 95% CI, 0.36 to 0.78), while bifidobacterium or saccharomyces did not have such effect. The results also indicated that only the mixed probiotics could reduce the risk of deaths (RR = 0.52, 95%CI, 0.34 to 0.80). Subgroup analysis for mortality revealed that probiotics had significant effect in Asian region (RR = 0.54, 95% CI, 0.37 to 0.80, P = 0.002) but not in non-Asian region (RR = 0.84, 95% CI, 0.66 to 1.08, P = 0.179).

Probiotics could significantly decrease the risk of stage II-III NEC and death. Compared to using single probiotics species, the application of combining different probiotics has a better efficacy in the prevention of stage II-III NEC and death, especially in the Asian population.

We aimed to compare probiotics with placebo for necrotizing enterocolitis in preterm infants and to evaluate the safety and effect and strict effect of specific probiotic genera.

Data recorded until January 2019 were searched, and relevant academic articles from PubMed, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were selected by two independent reviewers. Two reviewers independently included randomized controlled trials that compared probiotics and placebo in preterm infants. The outcomes included more than one of the following outcomes: incidence of necrotizing enterocolitis, necrotizing enterocolitis-related mortality, incidence of sepsis, and all-cause mortality. Two reviewers independently extracted data and assessed the risk of bias and quality of evidence.

We identified 34 eligible studies of 9161 participants. This meta-analysis showed an overall advantage of probiotics to prevent the incidence of necrotizing enterocolitis (3.54%) and gut-associated sepsis (15.59%), and decrease mortality (5.23%) in preterm infants. A probiotic mixture showed a huge advantage and vitality in preventing necrotizing enterocolitis (2.48%) and gut-associated sepsis (18.39%), and in reducing mortality (5.57%) in preterm infants.

The probiotic mixture showed advantages over the single strains to decrease the incidences of necrotizing enterocolitis and gut-associated sepsis, and mortality in preterm infants.

Previous studies have neglected to report the specific action of different probiotic genera in preterm infants. To evaluate the efficacy and safety of specific probiotic genera, we performed a network meta-analysis (NMA) to identify the best prevention strategy for necrotizing enterocolitis in preterm infants.

MEDLINE, PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials had been searched for randomized control trials reporting the probiotics strategy for premature infants.

We identified 34 eligible studies of 9161 participants. The intervention in the observation group was to add probiotics for feeding: Lactobacilli in 6 studies; Bifidobacterium in 8 studies; Bacillus in 1 study; Saccharomyces in 4 studies and probiotic mixture in 15 studies. This NMA showed a significant advantage of probiotic mixture and Bifidobacterium to prevent the incidence of necrotizing enterocolitis in preterm infants. A probiotic mixture showed effectiveness in reducing mortality in preterm infants.

The recent literature has reported a total of 5 probiotic strategies, including Bacillus, Bifidobacterium, Lactobacillus, Saccharomyces, and probiotic mixture. Our thorough review and NMA provided a piece of available evidence to choose optimal probiotics prophylactic strategy for premature infants. The results indicated that probiotic mixture and Bifidobacterium showed a stronger advantage to use in preterm infants; the other probiotic genera failed to show an obvious effect to reduce the incidence of NEC, sepsis and all-cause death. More trials need to be performed to determine the optimal probiotic treatment strategy to prevent preterm related complications.

Over the last few decades, numerous studies have evaluated probiotic use for the prevention of necrotising enterocolitis in preterm babies. Early 'proof of concept' studies evaluating whether probiotics are capable of colonising the preterm gut have translated into multiple observational studies, small and large randomised controlled trials. Some show evidence of benefit while others have produced disappointing results. In this paper, we review the history of probiotic use in preterm babies for NEC prevention in an attempt to explain why uncertainty exists and why this intervention has not been universally adopted into routine neonatal practice.

Probiotic use in the neonatal intensive care unit (NICU) has been linked to reduced rates of necrotizing enterocolitis in preterm infants. Currently, in the United States, probiotic use within the NICU is limited despite being commonly used in other countries.

To provide an overview of the current practices of using probiotics in preterm infants for the prevention of NEC in the NICU in preselected countries.

A comprehensive literature search was conducted on PubMed and clinicaltrials.gov. Also, studies from 2 recent meta-analyses on the topic were reviewed for inclusion. Selection criteria were as follows: studies involving preterm infants using probiotics in the NICU, reporting on the impact of probiotic use on the incidence of necrotizing enterocolitis, published within the last 10 years and in the English language, and originating from the United States, Canada, or any European country.

Twenty-three studies were selected. The most common types of probiotics used were Bifidobacterium infantis and Lactobacillus rhamnosus. The most common frequency of administration was daily or twice day. Duration ranged from 10 days to the entire NICU stay. The dosage was commonly 1 billion colony-forming units daily but ranged from 12 million daily to 12 billion per kilogram daily.

Examining the current practices of probiotic use in the NICU provides useful information as this adjunctive therapy rises in popularity.

Refining methods of probiotic research for necrotizing enterocolitis prevention will improve safety and effectiveness and provide a framework for future clinical trials.

Necrotizing enterocolitis (NEC) is one of the most common and serious gastrointestinal diseases in preterm infants. The aim of this systematic review examines the effects of probiotics on preventing NEC in very-low birth weight (VLBW) infants with a focus on the Bifidobacterium species and its strains. A systematic review of randomized trials and retrospective studies analyzing the use of probiotics to prevent NEC in VLBW infants was conducted using PubMed, Cochrane Central Registry of Controlled Trials, and Google Scholar (1996-2016). Trials reporting NEC involving preterm infants who were given Bifidobacterium alone in the first month of life were included in the systematic review. Nine studies were suitable for inclusion. Nine studies involving VLBW infants were analyzed for strain specific effects of Bifidobacterium for the prevention of NEC ≥ Stage II. B breve showed some benefit in infants < 34 weeks GA with relative risk (RR) of 0.43 (95% confidence interval [CI]: 0.21-0.87) p = 0.019, but not in neonates < 28 weeks. B lactis greatly reduced the incidence of NEC with a RR 0.11 (95% CI: 0.03-0.47), p = < 0.001. B bifidum was not widely studied but resulted in no cases of NEC. Bifidobacterium proved to be statistically significant in reducing the incidence of NEC in preterm infants.

A systematic review and meta-analysis was designed to evaluate the efficacy and safety of Bifidobacterium for preventing necrotizing enterocolitis (NEC) in preterm infants.

We searched the Cochrane Library, PubMed, EMBASE and Web of Science to December 2017. Risk ratio (RR) with 95% confidence intervals (CIs) were estimated to compare the outcomes of the groups. For the pooled RR estimating the incidence of NEC, we also performed subgroup analysis. Besides, sensitivity analysis was performed to examine the stability of the combined results. Two reviewers assessed trial quality and extracted data independently. The work has been reported in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR (Assessing the methodological quality of systematic reviews) Guidelines. All statistical analyses were performed using standard statistical procedures provided in Review Manager 5.2.

Twenty four randomized, placebo-controlled studies (N = 6155 participants) were included in this analysis, of which twenty two studies were used for assessing the efficacy of Bifidobacterium for preventing NEC and seventeen for assessing the safety (sepsis and death). When comparing Bifidobacterium groups with control groups, the relative risk of developing NEC (RR 0.38, 95% CI 0.25-0.58; P < 0.00001) or death (RR 0.74, 95% CI 0.60-0.92; P = 0.006) was significantly lower in the Bifidobacterium groups. No significant difference in the incidence of sepsis was found (RR 0.87, 95% CI 0.73-1.03; P = 0.11). In addition, significant results for NEC were also found in all subgroups we made.

Bifidobacterium may have a beneficial effect and be safe in preventing necrotizing enterocolitis in preterm infants.

Necrotizing enterocolitis (NEC) is a common severe gastrointestinal disease in preterm infants. The morbidity and mortality of NEC are negatively correlated with the gestational age and birth weight. In addition to causing a variety of gastrointestinal complications, NEC can also cause neurodevelopmental impairment. Recently, many studies have found that gut microbiome dysbiosis plays an important part in the pathogenesis of NEC. It is helpful to explore the relationship between gut microbiome and NEC for the early diagnosis and severity prediction of NEC. Researchers have paid much attention to the role of probiotics in reducing the morbidity and mortality of NEC in preterm infants. It's controversial as to whether probiotics is effective and safe in clinical application. This article will review the relationship between the development of gut microbiome and NEC in preterm infants, as well as the preventive effect of probiotics on NEC.

Several randomized controlled trials (RCTs) on the use of probiotics to reduce morbidity and mortality in preterm infants have provided inconsistent results. Although meta-analyses that group all of the used strains together are suggesting efficacy, it is not possible to determine the most effective strain that is more relevant to the clinician. We therefore used a network meta-analysis (NMA) approach to identify strains with greatest efficacy.

A PubMed search identified placebo-controlled or head-to-head RCTs investigating probiotics in preterm infants. From trials that recorded mortality, necrotizing enterocolitis, late-onset sepsis, or time until full enteral feeding as outcomes, data were extracted and Bayesian hierarchical random-effects models were run to construct a NMA.

Fifty-one RCTs involving 11,231 preterm infants were included. Most strains or combinations of strains were only studied in one or a few RCTs. Only 3 of 25 studied probiotic treatment combinations showed significant reduction in mortality rates. Seven treatments reduced necrotizing enterocolitis incidence, 2 reduced late-onset sepsis, and 3 reduced time until full enteral feeding. There was no clear overlap of strains, which were effective on multiple outcome domains.

This NMA showed efficacy in reducing mortality and morbidity only in a minority of the studied strains or combinations. This may be due to an inadequate number, or size, of RCTs, or due to a true lack of effect for certain species. Further large and adequately powered RCTs using strains with the greatest apparent efficacy will be needed to more precisely define optimal treatment strategies.

Necrotising enterocolitis (NEC) and late-onset sepsis remain important causes of death and morbidity in preterm babies. Probiotic administration might strengthen intestinal barrier function and provide protection; this is supported by published meta-analyses, but there is a lack of large well-designed trials.

To test the use of the probiotic Bifidobacterium breve strain BBG-001 to prevent NEC, late-onset sepsis and death in preterm babies while monitoring probiotic colonisation of participants.

Double-blind, randomised, placebo-controlled trial.

Recruitment was carried out in 24 hospitals, and the randomisation programme used a minimisation algorithm. Parents, clinicians and outcome assessors were blinded to the allocation.

Babies born between 23 and 30 weeks' gestation and randomised within 48 hours of birth. Exclusions included life-threatening or any gastrointestinal malformation detected within 48 hours of birth and no realistic chance of survival.

Active intervention: 1 ml of B. breve BBG-001 in one-eighth-strength infant formula Neocate(®) (Nutricia Ltd, Trowbridge, UK), (6.7 × 10(7) to 6.7 × 10(9) colony-forming units) per dose administered enterally. Placebo: 1 ml of one-eighth-strength infant formula Neocate. Started as soon as practicable and continued daily until 36 weeks' postmenstrual age.

Primary outcomes were an episode of bloodstream infection, with any organism other than a skin commensal, in any baby between 72 hours and 46 weeks' postmenstrual age; an episode of NEC Bell stage ≥ 2 in any baby; and death before discharge from hospital. Secondary outcomes included stool colonisation with B. breve.

In total, 654 babies were allocated to receive probiotic and 661 to receive placebo over 37 months from July 2010. Five babies were withdrawn; 650 babies from the probiotic group and 660 from the placebo group were included in the primary analysis. Baseline characteristics were well balanced. There was no evidence of benefit for the primary outcomes {sepsis: 11.2% vs. 11.7% [adjusted relative risk (RR) 0.97, 95% confidence interval (CI) 0.73 to 1.29]; NEC Bell stage ≥ 2: 9.4% vs. 10.0% [adjusted RR 0.93, 95% CI 0.68 to 1.27]; and death: 8.3% vs. 8.5% [adjusted RR 0.93, 95% CI 0.67 to 1.30]}. B. breve colonisation status was available for 1186 (94%) survivors at 2 weeks' postnatal age, of whom 724 (61%) were positive: 85% of the probiotic group and 37% of the placebo group. There were no differences for subgroup analyses by minimisation criteria and by stool colonisation with B. breve at 2 weeks. No harms associated with the interventions were reported.

Cross-colonisation of the placebo arm could have reduced statistical power and confounded results; analyses suggest that this did not happen.

This is the largest trial to date of a probiotic intervention. It shows no evidence of benefit and does not support routine use of probiotics for preterm infants.

The increasing understanding of the pathogenesis of NEC and sepsis will inform the choice of probiotics for testing and better define the target population. Future Phase III trials should incorporate monitoring of the quality and viability of the intervention and colonisation rates of participants; cluster design should be considered.

Current Controlled Trials ISRCTN05511098 and EudraCT 2006-003445-17.

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 66. See the NIHR Journals Library website for further project information.

Antibiotics can disturb gastrointestinal microbiota which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live microbial preparations that, when administered in adequate amounts, may confer a health benefit to the host, and are a potential C. difficile prevention strategy. Recent clinical practice guidelines do not recommend probiotic prophylaxis, even though probiotics have the highest quality evidence among cited prophylactic therapies.

To assess the efficacy and safety of probiotics for preventing C.difficile-associated diarrhea (CDAD) in adults and children.

We searched PubMed, EMBASE, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 21 March 2017. Additionally, we conducted an extensive grey literature search.

Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion.

Two authors (independently and in duplicate) extracted data and assessed risk of bias. The primary outcome was the incidence of CDAD. Secondary outcomes included detection of C. difficile infection in stool, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the risk ratio (RR) and corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. Continuous outcomes (e.g. length of hospital stay) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group, we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analyses were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias as well as a post hoc subgroup analysis on baseline risk of CDAD (low 0% to 2%; moderate 3% to 5%; high > 5%). The overall quality of the evidence supporting each outcome was independently assessed using the GRADE criteria.

Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of probiotics, or studies at high versus low risk of bias. However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the probiotics group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance.

Based on this systematic review and meta-analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that probiotics are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that probiotics are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk ≤5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics.

We performed an updated meta-analysis incorporating the results of recent randomised controlled trials (RCTs) to measure the effectiveness of probiotic supplementation in preventing necrotising enterocolitis (NEC) and death in very low-birth-weight (VLBW) infants, and to investigate any differences in efficacy by probiotic agent. Using meta-regression analysis, we assessed the contribution of other measured variables on the overall effect size and between-study variability.

Overall, probiotics lead to significant reductions in NEC incidence and mortality in VLBW infants. Differences in probiotic agents and the influence of prenatal steroids and feeding regimens may explain the differences in outcomes between studies.

Probiotics are increasingly used as a supplement to prevent adverse health outcomes in preterm infants. We conducted a systematic review, meta-analysis, and subgroup analysis of findings from randomized controlled trials (RCTs) to assess the magnitude of the effect of the probiotics on health outcomes among very-low-birth-weight (VLBW) infants. Relevant articles from January 2003 to June 2017 were selected from a broad range of databases, including Medline, PubMed, Scopus, and Embase. Studies were included if they used an RCT design, involved a VLBW infant (birthweight <1500 g or gestational age <32 wk) population, included a probiotic intervention group, measured necrotizing enterocolitis (NEC) as a primary outcome, and measured sepsis, mortality, length of hospital stay, weight gain, and intraventricular hemorrhage (IVH) as additional outcomes. The initial database search yielded 132 potentially relevant articles and 32 (n = 8998 infants) RCTs were included in the final meta-analysis. Subgroup analysis was used to evaluate the effects of the moderators on the outcome variables. In the probiotics group, it was found that NEC was reduced by 37% (95% CI: 0.51%, 0.78%), sepsis by 37% (95% CI: 0.72%, 0.97%), mortality by 20% (95% CI: 0.67%, 0.95%), and length of hospital stay by 3.77 d (95% CI: -5.94, -1.60 d). These findings were all significant when compared with the control group. There was inconsistent use of strain types among some of the studies. The results indicate that probiotic consumption can significantly reduce the risk of developing medical complications associated with NEC and sepsis, reduce mortality and length of hospital stay, and promote weight gain in VLBW infants. Probiotics are more effective when taken in breast milk and formula form, consumed for <6 wk, administered with a dosage of <10⁹ CFU/d, and include multiple strains. Probiotics are not effective in reducing the incidence of IVH in VLBW infants.

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.

Colonization of the extremely preterm infant's gastrointestinal tract and skin begins in utero and is influenced by a variety of factors, the most important including gestational age and environmental exposures. The composition of the intestinal and skin microbiota influences the developing innate and adaptive immune responses with short-term and long-term consequences including altered risks for developing necrotizing enterocolitis, sepsis, and a wide variety of microbe-related diseases of children and adults. Alteration of the composition of the microbiota to decrease disease risk is particularly appealing for this ultra-high-risk cohort that is brand new from an evolutionary standpoint.

Necrotizing enterocolitis (NEC) is a serious multifactorial gastrointestinal disease which is often discovered in premature infants. Various additives have been used to prevent NEC; yet, their relative efficacy and safety remain disputed. This study aims to compare the efficacy and safety of 5 food additives, namely, probiotics, probiotics + fructo-oligosaccharides, pentoxifylline, arginine, and lactoferrin in preventing NEC in neonates.

Embase, PubMed, and Cochrane Library had been searched for all eligible randomized control trials. Odds ratios (ORs) were estimated for dichotomous data and mean differences with 95% credible intervals (CrIs) were estimated for continuous data. Surface under the cumulative ranking curve was used to rank efficacy and safety of the prevention methods on each endpoint.

A total of 27 eligible studies with 4649 preterm infants were included in this network meta-analysis (NMA), and the efficacy and safety of 5 food additives were evaluated. Probiotic and arginine exhibited better preventive efficacy compared with placebo (OR = 0.50, 95% CrIs: 0.32-0.73; OR = 0.30, 95% CrIs: 0.12-0.73, respectively). Only probiotic achieved a considerable decrease in the risk of mortality compared to placebo (OR = 0.68, 95% CrIs: 0.46-0.98). NEC patients with lactoferrin appeared to have lower incidence of sepsis than those of placebo (OR = 0.13, 95% CrIs: 0.03-0.61) or probiotic (OR = 0.18, 95% CrIs: 0.03-0.83).

Based on this NMA, probiotics had the potential to be the most preferable additive, since it exhibited a significant superiority for NEC and mortality as well as a relatively balanced performance in safety.

To measure the efficacy of a probiotic formulation on time to reach full enteral feeds in VLBW (very low birth weight) newborns.

Blinded randomized control trial.

A tertiary care neonatal intensive care unit (NICU) in Southern India between August 2012 to November 2013.

104 newborns with a birth weight of 750-1499 g on enteral feeds.

Probiotic group (n=52) received a multicomponent probiotic formulation of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum and Saccharomyces boulardii once a day at a dose of 1.25×109 CFU from the time of initiation of enteral feeds till discharge and the control group (n=52) received only breast milk.

Time to reach full enteral feeds (150 mL/kg/day).

The mean (SD) time to reach full enteral feeding was 11.2 (8.3) days in probiotic vs. 12.7 (8.9) in no probiotic group; (P=0.4), and was not significantly different between the two study groups. There was a trend towards lower necrotizing enterocolitis in the probiotic group (4% vs. 12%).

Probiotic supplementation does not seem to result in significant improvement of feed tolerance in VLBW newborns.

Some oral probiotics have been shown to prevent necrotizing enterocolitis (NEC) and decrease mortality effectively in preterm very low birth weight (PVLBW) infants. However, it is unclear whether a single probiotic or a mixture of probiotics is most effective for the prevention of NEC.

A meta-analysis was conducted by reviewing the most up to date literature to investigate whether multiple strains probiotics are more effective than a single strain in reducing NEC and death in PVLBW infants.

Relevant studies were identified by searches of the MEDLINE, EMBASE, and Cochrane CENTRAL databases, from 2001 to 2016.

The inclusion criteria were randomized controlled trials of any enteral probiotic supplementation that was initiated within the first 7 days and continued for at least 14 days in preterm infants (≤ 34 weeks' gestation) and/or those of a birth weight ≤1500 g.

A total of 25 trials (n = 7345 infants) were eligible for inclusion in the meta-analysis using a fixed-effects model. Multiple strains probiotics were associated with a marked reduction in the incidence of NEC, with a pooled OR of 0.36 (95% CI, 0.24-0.53; P < .00001). Single strain probiotic using Lactobacillus species had a borderline effect in reducing NEC (OR of 0.60; 95% CI 0.36-1.0; P = .05), but not mortality. Multiple strains probiotics had a greater effectiveness in reducing mortality and were associated with a pooled OR of 0.58 (95% CI, 0.43-0.79; P = .0006). Trials using single strain of Bifidobacterium species and Saccharomyces boulardii did not reveal any beneficial effects in terms of reducing NEC or mortality.

This updated report found that multiple strains probiotics appear to be the most feasible and effective strategy for the prevention of NEC and reduction of mortality in PVLBW neonates. Further clinical trials should focus on which probiotic combinations are most effective.

Probiotic administration to preterm infants has the potential to prevent necrotising enterocolitis (NEC). Data from randomised controlled trials (RCT) are conflicting but meta-analyses seem to support this intervention. To date, these analyses have not focused on surgical NEC. We aimed to determine the effect of probiotic administration to preterm infants on prevention of surgical NEC.

A systematic review of RCTs of probiotic administration to preterm infants was performed. Studies were included if RCT outcomes included any of (1) Bell's stage 3 NEC; (2) surgery for NEC; and (3) deaths attributable to NEC. Article selection and data extraction were performed independently by two authors; conflicts were adjudicated by a third author. Data were meta-analysed using Review Manager V.5.3. A random effects model was decided on a priori because of the heterogeneity of study design; data are risk ratio (RR) with 95% CI.

Thirty-five RCTs reported NEC as an outcome. Seventeen reported surgical NEC; all RCTs were included. A variety of probiotic products was administered across studies. Description of surgical NEC in most studies was poor. Only 6/16 specifically reported incidence of surgery for NEC, 12/17 Bell's stage 3 and 13/17 NEC-associated mortality. Although there was a trend towards probiotic administration reducing stage 3 NEC, this was not significant (RR 0.74 (0.52-1.05), p=0.09). There was no effect of probiotics on the RR of surgery for NEC (RR 0.84 (0.56-1.25), p=0.38). Probiotics did, however, reduce the risk of NEC-associated mortality (RR 0.56 (0.34-0.93), p=0.03).

Despite 35 RCTs on probiotic prevention of NEC, evidence for prevention of surgical NEC is not strong, partly due to poor reporting. In studies included in this meta-analysis, probiotic administration was associated with a reduction in NEC-related mortality.

Over the last few years, probiotics have been one of the most studied interventions in neonatal medicine.

The aim of this work was to analyse all studies (randomized controlled trials, RCTs, and observational studies) assessing the use of probiotics in very low birth weight (VLBW) preterm infants.

A systematic literature search was conducted using PubMed, Embase, Cochrane Library, and Web of Science. The data from RCTs and observational studies were pooled and analysed separately.

RCTs and observational studies that enrolled VLBW infants with enteral administration of probiotics were considered. Extracted study data included probiotic characteristics and at least 1 clinical outcome (necrotizing enterocolitis [NEC], late-onset sepsis or all-cause mortality).

Forty-four studies were eligible for our review: 30 RCTs and 14 observational studies. Severe NEC rates (stage II or more) and all-cause mortality were reduced among the probiotic groups in both the RCTs (RR 0.57, 95% CI 0.47-0.70, and RR 0.77, 95% CI 0.65-0.92, respectively) and the observational studies (RR 0.51, 95% CI 0.37-0.70, and RR 0.71, 95% CI 0.62-0.81, respectively). Furthermore, there was a 12% reduction in the risk of sepsis in RCTs and a 19% reduction in observational studies. The meta-analysis of observational studies showed a reduction in the risk of NEC in extremely low birth weight infants. However, this was not statistically significant.

This meta-analysis of RCT and observational studies found that the use of probiotics was beneficial for the prevention of severe NEC, late-onset sepsis, and all-cause mortality in VLBW infants.

Common among preterm, very low birth weight (VLBW) and extremely low birth weight (ELBW) infants, necrotizing enterocolitis (NEC) is a gastrointestinal, infectious disease that remains a leading cause of morbidity and mortality among this high-risk population. To combat this devastating condition, research efforts have been redirected from treatment toward prevention strategies. Although there are several proposed risk-reduction strategies, one intervention gaining support is the administration of prophylactic enteral probiotics. Regardless of growing evidentiary support and a benign safety profile, neonatal providers have yet to embrace this therapy. This article provides an overview of the proposed benefits of probiotics, focusing on their role as a NEC prevention strategy. A review of several sentinel research studies targeting preterm, VLBW, and ELBW infants is provided. Considerations for ongoing research are reviewed. Finally, two evidence-based NEC prevention probiotics protocols are presented.

Data from multiple clinical trials, mostly conducted outside the US, indicate that probiotic prophylaxis is an effective intervention for prevention of necrotizing enterocolitis (NEC) in preterm infants. Probiotics are routinely used in many countries. However, in the US, probiotic use in preterm infants is limited (6.7% of very low birth weight (VLBW) infants in the US were exposed to probiotics in 2014, Vermont Oxford Network (VON)). Probiotic products are often considered in 'generic' terms, but considerable variation exists between commercially available probiotics in terms of their quantity and quality. The study objectives were to identify the probiotic products used in VLBW infants within the US, and to determine whether their use was supported by reliable evidence.

A phone survey of all neonatal intensive care units (NICU) participating in VON within the US was conducted between May and September 2015 to identify NICUs that are using probiotics in VLBW infants. Data was collected regarding specific probiotic brands, timing, dose and duration of probiotic use. An evidence based literature search, limited to randomized controlled trials in VLBW infants, was conducted to determine whether the use of identified probiotics were supported by reliable evidence.

There was a 70.3% (500/711) response rate to the phone survey. During the survey period, 14.0% of NICUs were using probiotics in VLBW infants (70/500). Probiotics were routinely given to all VLBW infants in 8.8% (44/500) NICUs, while it was given in selected VLBW infants in 5.2% (26/500) of NICUs. The common indications for selective use of probiotics were feeding intolerance and antibiotic use. Sixteen commercial probiotics products were identified through the phone survey. Probiotic products most commonly used were Culturelle (27.1%), Biogaia (14.3%), Gerber Soothe (14.3%) and Florababy (8.6%). The literature search identified evidence that evaluated 4/16 probiotic products identified (Culturelle, Align, Biogaia and ABC Dophilus). Only ABC Dophilus was reported to have a protective effect against NEC, but is used sparingly in US NICUs (2.9%).

The probiotics use in VLBW infants within the US is increasing, but is still limited. There was no evidence for safety or efficacy of 90% of the probiotics currently used in US NICUs, and therefore, caution is warranted.