Routine Probiotic Supplementation Research Articles

Neonatal outcomes following introduction of routine probiotic supplementation to very preterm infants.

To evaluate the combined outcome of death and/or severe grade necrotising enterocolitis (NEC) in very preterm infants admitted to Cork University Maternity Hospital, Ireland, before and after introduction of routine supplementation with Bifidobacterium bifidum and Lactobacillus acidophilus probiotics (Infloran®). A retrospective study of infants <32 weeks gestation and <1500g surviving beyond 72 hours of life was performed. Two 6-year epochs; pre-probiotics (Epoch 1: 2008-2013) and with probiotics (Epoch 2: 2015-2020), were evaluated. The primary outcome was defined as death after 72 hours or NEC Bell stage 2a or greater. Seven-hundred-and-forty-four infants were included (Epoch 1: 391, Epoch 2: 353). The primary outcome occurred in 67 infants (Epoch 1: 37, Epoch 2: 30, p=.646)). After adjustment, the difference was significant ((OR(95% CI): 0.53 (0.29 to 0.97), p=.038). Differences between epochs did not depend on gestational age group (< 28 weeks; ≥ 28 weeks). There was an associated reduction of the composite outcome of severe grade NEC and/or death, after adjustment for confounding variables, with introduction of routine administration of a B. bifidum and L. acidophilus probiotic at our institution.

Benefits of routine probiotic supplementation in preterm infants.

We introduced routine probiotic supplementation (RPS) of preterm infants in June 2012. We previously reported that RPS reduced the incidence of necrotising enterocolitis (NEC) and mortality in such infants. In this study, we assessed if the benefits of RPS were sustained for infants in the current era. We compared the outcomes of preterm infants in recent epoch 3 (RPS, 1st June 2014 to 31st December 2019) versus epoch 2 (RPS, 1st June 2012 to 31st May 2014) and epoch 1 (no RPS, 1st December 2008 to 30th November 2010). Multiple logistic and Cox regression models were used to compare the outcomes. There were 645 infants in epoch 1, 712 in epoch 2 and 1715 in epoch 3. Age at full feeds was significantly lower in epoch 3 vs. 2 and epoch 3 vs. 1 in infants <28 weeks of gestation. NEC and late-onset sepsis (LOS) were significantly lower in epoch 3 vs. 1 in infants <28 weeks. LOS and age at full feeds were significantly lower in epoch 3 vs. 2 and epoch 3 vs. 1 in infants with gestation 28 to 32 weeks. The benefits associated with RPS were sustained during epoch 3.

Routine Administration of a Multispecies Probiotic Containing Bifidobacterium and Lactobacillus to Very Low Birth Weight Infants Had No Significant Impact on the Incidence of Necrotizing Enterocolitis.

Background: Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity in preterm infants, and prevention and treatment strategies have remained largely unchanged over the past several decades. As understanding of the microbiome has increased, probiotics have been hypothesized as a possible strategy for decreasing rates of NEC, and several studies have noted significant decreases in rates of NEC after initiation of probiotics in preterm infants. However, a recent AAP report cited caution on the use of probiotic use in part because studies of probiotic use in ELBW infants are lacking. As our unit began routine use of probiotics for all infants <33 weeks in 2015 and we are a leading institution for intact survival of ELBW infants, we attempted to answer if probiotic use can impact the rate of NEC in VLBW and ELBW infants.Methods: We conducted a single-center retrospective chart review of infants with modified Bell's stage ≥2a NEC for the 4 years prior to and 5 years after initiation of a protocol involving routine supplementation of a multispecies probiotic to premature infants at the University of Iowa, Stead Family Children's Hospital. The primary outcome measures were rates of modified Bell's stage ≥2a NEC and all-cause pre-discharge mortality at our institution before and after initiation of routine probiotic supplementation in 2015.Results: In our institution, neither the rates of modified Bell's stage ≥2a NEC, nor the rates of all-cause mortality were significantly altered in very low birth weight (VLBW) infants by the initiation of routine probiotic use (NEC rates pre-probiotic 2.1% vs. post-probiotic 1.5%; all-cause mortality rates pre-probiotic 8.4% vs. post-probiotic 7.4%). Characteristics of our two cohorts were overall similar except for a significantly lower 5-minute APGAR score in infants in the post-probiotic epoch (pre-probiotic 8 vs. post-probiotic 6 p = 0.0316), and significantly more infants in the post-probiotic epoch received probiotics (pre-probiotics 0% vs. post-probiotics 65%; p < 0.0001). Similarly, probiotic use had no impact on the incidence of NEC when we restricted our data to only extremely low birth weight (ELBW) infants (pre-probiotics 1.6% vs post-probiotics 4.1%). When we restricted our analysis to only inborn infants, probiotics still had no impact on NEC rates in VLBW infants (1.5% pre- and 1.1% post-probiotic, p = 0.61) or ELBW infants (2% pre- and 2.1% post-probiotic, p = 0.99)Conclusions: Contrary to other studies, we found no significant difference in rates of modified Bell's stage ≥2a NEC or all-cause pre-discharge mortality in VLBW infants following routine administration of a multispecies probiotic supplement.

Arguments against routine administration of probiotics for NEC prevention.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among premature neonates. Although randomized trials have shown that probiotics may be efficacious in the prevention of NEC, their use has not been universally adopted in the neonatal intensive care unit (NICU). Caveats regarding routine probiotic supplementation for the prevention of NEC are summarized in this review. Accumulating evidence indicates that prophylactic probiotic supplementation in preterm infants can reduce the incidence of NEC. However, substantial knowledge gaps, regulatory issues, and implementation challenges should be addressed before probiotics are introduced as standard of care for all preterm neonates. Limitations of published trial data have made it challenging to define regimens that optimize efficacy and safety in specific patient subgroups. Moreover, the current probiotic market lacks rigorous regulatory oversight, which could raise concerns about the quality and safety of probiotic products. Finally, implementation pitfalls include risks of cross-colonization and resource requirements to monitor and mitigate potential adverse events. Probiotics have shown promise in the prevention of NEC. However, there is insufficient evidence to guide the selection of optimal regimens. Furthermore, issues related to regulatory and institutional oversight should be addressed before supplementation is routinely implemented in NICUs.

A Quality Improvement Intervention to Reduce Necrotizing Enterocolitis in premature infants with Probiotic Supplementation.

We aimed to reduce NEC rate by 30% by the end of 2016. We used the Institute of Healthcare Improvement model and typical QI tools, including teamwork, process organizing tools, and evidence-based review, to assist in our selection of supplementation of Lactobacillus reuteri probiotic. We used education, process mapping, process control statistics, and forcing mechanism to implement the changes. In addition to reducing NEC rates, our additional outcome measures were sepsis, mortality, sepsis evaluations, feeding intolerance, growth, days of both antimicrobials, and parenteral nutrition use. Process measures were compliance with probiotics supplementation policy and balancing measures were sepsis rates and feeding intolerance. NEC rates decreased from 4.4% to the current 1.7%, and in a pre/post-intervention analysis, the results were significant in all patient subcategories. We did not demonstrate a reduction in mortality. No adverse events occurred. Feeding intolerance episodes and days nil-per-os decreased with no differences in growth at discharge. These results continued over 2 years, and this practice has already spread to several neonatal intensive care units in Ontario, Canada. We utilized QI methods and tools to implement a successful practice change of routine probiotic supplementation to reduce NEC rates in preterm infants. We suggest considering this intervention as a successful means to prevent this serious illness.

Outcomes in preterm small versus appropriate for gestation infants after Bifidobacterium breve M-16 V supplementation

Introduction: Fecal bifidobacteria response after Bifidobacterium breve M-16 V supplementation was comparable in preterm small (SGA) versus appropriate for gestational age (AGA) infants.Objectives: To compare clinical outcomes between preterm SGA versus AGA infants after routine probiotic supplementation (RPS) with Bifidobacterium breve M-16V (3 × 109 CFU/day).Design: Retrospective cohort study (June 2012–August 2015) comparing outcomes between preterm (<34 weeks, subgroup: <29 weeks) SGA versus AGA infants after RPS with B. breve M-16 V using multivariable regression analysis. Primary outcome: necrotizing enterocolitis (NEC)≥Stage II/all-cause mortality. Secondary outcomes: NEC ≥ Stage II, all-cause mortality, late onset sepsis (LOS), postnatal age at full feeds (PAFF).Results: Outcomes in inborn 1380/1481 (162 SGA versus 1218 AGA) admissions were analyzed. Primary outcome “NEC ≥ Stage II /all-cause mortality” was higher in SGA versus AGA infants <29 weeks (21 versus 12%; p = .040), and showed trend toward reduction (8 versus 6%; p = .057) in AGA <34 weeks. NEC ≥ Stage II, LOS, and all-cause mortality was comparable in SGA versus AGA infants <34 weeks (3 versus 2, 9 versus 8, 9% versus 6%) and <29 weeks (5 versus 4, 16 versus 9, 18% versus 19%), respectively. Median (IQR) PAFF was significantly higher in SGA versus AGA infants <34 weeks (8 (6–12) versus 7 (5–10) days), and <29 weeks (14 (12–17) versus 11 (8–16) days).Conclusions: NEC, LOS and all-cause mortality rates were similar in preterm SGA versus AGA infants after RPS with Bifidobacterium breve M-16 V, but PAFF was higher in SGA infants.

Factors Associated with Time to Full Feeds in Preterm Very Low Birth Weight Infants.

Feeding intolerance prolongs time to full feeds (TFFs) in preterm infants. We studied factors associated with TFF in preterm infants on standardized feeding regimen (SFR) and routine probiotic supplementation (RPS). This is a prospective cohort study of preterm infants ≤1500g. Pearson's correlation, Mann-Whitney test and multivariate analysis were used. In total, 37 of 304 admitted infants died before reaching full feeds. Median (interquartile range) gestation, birth weight and TFF were 31.4 (30-33.05) weeks, 1210 (1066-1400) g and 11 (8-15) days, respectively. Gestation and birthweight were inversely correlated with TFF, whereas low Apgar's, sepsis, patent ductus arteriosus (PDA) and respiratory distress syndrome were directly correlated with TFF. Growth-restricted infants had significantly shorter TFF vs. appropriate for gestational age infants, probably because of higher gestation. On multivariate analysis gestation, sepsis and PDA were significant predictors of TFF. In preterm infants managed with SFR and RPS, gestation had inverse correlation with TFF, whereas sepsis and PDA had direct correlation with TFF.

Standardized feeding and probiotic supplementation for reducing necrotizing enterocolitis in preterm infants in a resource limited set up.

Necrotizing enterocolitis (NEC ≥ Stage II) is associated with high mortality and morbidity in preterm infants. To assess if introduction of standardized feeding regimen (SFR) and routine probiotic supplementation (RPS) was associated with reduced incidence of NEC in preterm infants in our nursery in a resource limited set up. This was a retrospective cohort study assessing the incidence of NEC ≥ Stage II before (Epoch 1: N = 144) vs. after (Epoch 2, N = 144) implementation of SFR and RPS in preterm infants < 35 weeks. The median (IQR) gestation and birth weight in epoch 1 and epoch 2 was [32 (30, 33.5) vs. 31.5 (30, 34) weeks, p = 0.829], and [1350 (1100, 1700) vs. 1370 (1110, 1550) g, p = 0.363] respectively. Both groups had predominantly outborn infants (Epoch 1: 79.2% vs. Epoch 2: 78.2%; p = 1.00). Multivariate analysis after adjusting for potential confounders found a significantly lower incidence of NEC ≥ Stage II after implementing SFR and RPS (Epoch 1: 17.4% vs. Epoch 2:9.0%, adjusted odds ratio aOR: 0.19; 95% CI: 0.05, 0.71, p = 0.013). The incidence of the composite outcome of 'NEC or Mortality' was also significantly lower after the intervention (Epoch 1: 21.5% vs. Epoch 2: 14.6%; aOR 0.24, 95% CI: 0.07, 0.85, p = 0.027). Introduction of SFR and RPS was associated with significant reduction in NEC ≥ Stage II and the composite outcome of NEC ≥ Stage II /mortality in preterm infants.

Benefits of Bifidobacterium breve M-16V Supplementation in Preterm Neonates - A Retrospective Cohort Study.

BackgroundSystematic reviews of randomised controlled trials report that probiotics reduce the risk of necrotising enterocolitis (NEC) in preterm neonates.AimTo determine whether routine probiotic supplementation (RPS) to preterm neonates would reduce the incidence of NEC.MethodsThe incidence of NEC ≥ Stage II and all-cause mortality was compared for an equal period of 24 months ‘before’ (Epoch 1) and ‘after’ (Epoch 2) RPS with Bifidobacterium breve M-16V in neonates <34 weeks. Multivariate logistic regression analysis was conducted to adjust for relevant confounders.ResultsA total of 1755 neonates (Epoch I vs. II: 835 vs. 920) with comparable gestation and birth weights were admitted. There was a significant reduction in NEC ≥ Stage II: 3% vs. 1%, adjusted odds ratio (aOR) = 0.43 (95%CI: 0.21–0.87); ‘NEC ≥ Stage II or all-cause mortality’: 9% vs. 5%, aOR = 0.53 (95%CI: 0.32–0.88); but not all-cause mortality alone: 7% vs. 4%, aOR = 0.58 (95% CI: 0.31–1.06) in Epoch II. The benefits in neonates <28 weeks did not reach statistical significance: NEC ≥ Stage II: 6% vs. 3%, aOR 0.51 (95%CI: 0.20–1.27), ‘NEC ≥ Stage II or all-cause mortality’, 21% vs. 14%, aOR = 0.59 (95%CI: 0.29–1.18); all-cause mortality: 17% vs. 11%, aOR = 0.63 (95%CI: 0.28–1.41). There was no probiotic sepsis.ConclusionRPS with Bifidobacterium breve M-16V was associated with decreased NEC≥ Stage II and ‘NEC≥ Stage II or all-cause mortality’ in neonates <34 weeks. Large sample size is required to assess the potential benefits of RPS in neonates <28 weeks.

Influence of Routine Probiotic Supplementation on the Incidence of Necrotizing Enterocolitis and Late Onset Sepsis

Influence of Routine Probiotic Supplementation on the Incidence of Necrotizing Enterocolitis and Late Onset Sepsis

O-041 Intestinal Microbiota Diversity In Premature Neonates After Supplementation With Probiotic Lactobacillus And Bifidobacterium

Purpose Routine probiotic supplementation with Bifiborm ® ( Lactobacillus rhamnosus and Bifidobacterium lactis) in infants with gestational age below 30 weeks was introduced in April 2010 at the Department of Neonatology, Rigshospitalet to reduce the risk of NEC. We aimed to investigate the presence of the probiotic agents as well as potential changes in the total microbiota in the stools collected in two cohorts of infants, before and after the introduction of routine probiotics. Methods The first cohort (“control cohort”) was recruited from September 2006 to January 2009; the second cohort (“probiotic cohort”) was recruited from May 2010 to October 2011. Stool samples were collected by nurses as part of routine care at postnatal day 0–5 (sample 1), day 10 (sample 2) and day 30 (sample 3). The total number of samples was 446 in the control cohort and 225 in the probiotic cohort. All the stool samples were examined by conventional culture, tested by PCR for the 16S DNA of the two probiotic agents, as well as denaturing gel gradient electrophoresis (DGGE). The band patterns from DGGE were subjected to principal component analysis (PCA). Results In the probiotic cohort 82% was PCR positive for L. rhamnosus , 34% was positive for B. lactis in contrast to 6% and 3% in the control cohort. The PCA from the DGGE results did discriminate the two groups with a p –70 . This was dominantly caused by a strong first component representing mainly the total of number of bands, with no dominant pattern. Culture showed also a higher number of organisms (pp –22 ) with no specific bacteria. Conclusion L. rhamnosus and B. lactis are not naturally present in the stool of neonates. Administration of probiotics resulted in the presence of the probiotic organisms in the stools and more importantly a profound increase in diversity of the intestinal microbiota. No specific bacteria were seen to be favoured by the probiotic supplementation.

Effect of Bifidobacterium breve M-16V Supplementation on Fecal Bifidobacteria in Preterm Neonates - A Randomised Double Blind Placebo Controlled Trial

BackgroundProbiotic supplementation significantly reduces the risk of necrotising enterocolitis (NEC) and all cause mortality in preterm neonates. Independent quality assessment is important before introducing routine probiotic supplementation in this cohort.AimTo assess product quality, and confirm that Bifidobacterium breve (B. breve) M-16V supplementation will increase fecal B. breve counts without adverse effects.Methods and ParticipantsStrain identity (16S rRNA gene sequencing), viability over 2 year shelf-life were confirmed, and microbial contamination of the product was ruled out. In a controlled trial preterm neonates (Gestation <33 weeks) ready to commence or on feeds for <12 hours were randomly allocated to either B. breve M-16V (3×109 cfu/day) or placebo (dextrin) supplementation until the corrected age 37 weeks. Stool samples were collected before (S1) and after 3 weeks of supplementation (S2) for studying fecal B. breve levels using quantitative PCR (Primary outcome). Secondary outcomes included total fecal bifidobacteria and NEC≥Stage II. Categorical and continuous outcomes were analysed using Chi-square and Mann-Whitney tests, and McNemar and Wilcoxon signed-rank tests for paired comparisons.ResultsA total of 159 neonates (Probiotic: 79, Placebo: 80) were enrolled. Maternal and neonatal demographic characteristics were comparable between the groups. The proportion of neonates with detectable B. breve increased significantly post intervention: Placebo: [S1:2/66 (3%), S2: 25/66 (38%), p<0.001] Probiotic: [S1: 29/74 (40%), S2: 67/74 (91%), p<0.001].Median S1 B. breve counts in both groups were below detection (<4.7 log cells.g−1), increasing significantly in S2 for the probiotic group (log 8.6) while remaining <4.7 log in the control group (p<0.001). There were no adverse effects including probiotic sepsis and no deaths. NEC≥Stage II occurred in only 1 neonate (placebo group).Conclusion B. breve M-16V is a suitable probiotic strain for routine use in preterm neonates.Trial RegistrationAustralia New Zealand Clinical Trial Registry ACTRN 12609000374268

1382 Introducing Routine Probiotics for Preterm Neonates - Nepean Hospital Sydney Australia Approach

BackgroundProbiotic supplementation significantly reduces the risk of mortality and ≥ Stage II necrotising enterocolitis in preterm neonates. (Deshpande et al Lancet 2007, Pediatrics 2010). Based on the current evidence, experts...

Evidence-based guidelines for use of probiotics in preterm neonates.

BackgroundCurrent evidence indicates that probiotic supplementation significantly reduces all-cause mortality and definite necrotising enterocolitis without significant adverse effects in preterm neonates. As the debate about the pros and cons of routine probiotic supplementation continues, many institutions are satisfied with the current evidence and wish to use probiotics routinely. Because of the lack of detail on many practical aspects of probiotic supplementation, clinician-friendly guidelines are urgently needed to optimise use of probiotics in preterm neonates.AimTo develop evidence-based guidelines for probiotic supplementation in preterm neonates.MethodsTo develop core guidelines on use of probiotics, including strain selection, dose and duration of supplementation, we primarily used the data from our recent updated systematic review of randomised controlled trials. For equally important issues including strain identification, monitoring for adverse effects, product format, storage and transport, and regulatory hurdles, a comprehensive literature search, covering the period 1966-2010 without restriction on the study design, was conducted, using the databases PubMed and EMBASE, and the proceedings of scientific conferences; these data were used in our updated systematic review.ResultsIn this review, we present guidelines, including level of evidence, for the practical aspects (for example, strain selection, dose, duration, clinical and laboratory surveillance) of probiotic supplementation, and for dealing with non-clinical but important issues (for example, regulatory requirements, product format). Evidence was inadequate in some areas, and these should be a target for further research.ConclusionWe hope that these evidence-based guidelines will help to optimise the use of probiotics in preterm neonates. Continued research is essential to provide answers to the current gaps in knowledge about probiotics.

Progress in the field of probiotics: year 2011

The interest and scope for research in the field of probiotics has significantly widened in recent years. This brief review covers the significant advances in the field of probiotics. These include conclusive evidence for the benefits of probiotics in preventing all cause mortality and necrotizing enterocolitis (NEC) in preterm very low birth weight (VLBW) neonates, understanding the role of probiotics as vaccine adjuvants, and in modulating inflammatory bowel diseases, bowel cancer, type 1 diabetes mellitus, obesity, high cholesterol levels, and bacterial resistance. Other areas of progress include understanding the role of probiotics in oral health and ageing. Current evidence will lead to routine probiotic supplementation to prevent all cause mortality and NEC in preterm VLBW neonates. Probiotics may also become novel agents as vaccine adjuvants, and in dealing with major public health issues such as obesity, type I diabetes mellitus, and poor oral health. Research in applications of probiotics in food products will rationalize product development, and health claims. As new frontiers continue to be explored the challenges to the basis of the hygiene hypothesis will influence further developments in the field of probiotics.