Prophylactic Probiotic Supplementation for Preterm Neonates—A Systematic Review and Meta-Analysis of Nonrandomized Studies

Abstract

Systematic review and meta-analyses of randomized controlled trials (RCTs) show that probiotics reduce the risk of necrotizing enterocolitis (NEC ≥ Stage II), late onset sepsis (LOS), all-cause mortality, and feeding intolerance in preterm neonates. Data from observational studies is important to confirm probiotic effects in clinical practice. We aimed to compare outcomes before and after implementing routine probiotic supplementation (RPS) in preterm neonates (<37 weeks of gestation) by performing a systematic review of non-RCTs using Cochrane methodology. Databases including PubMed, The Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Cochrane Central library, and Google Scholar were searched in May 2020. A meta-analysis was performed using a random effects model. Categorical measure of effect size was expressed as OR and 95% CI. Statistical heterogeneity was assessed by the chi-squared test, I2 statistic. The level of evidence (LOE) was summarized using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) guidelines. Primary outcomes were NEC ≥ Stage II, LOS, and all-cause mortality. Secondary outcomes included probiotic sepsis. Thirty good-quality non-RCTs (n = 77,018) from 18 countries were included. The meta-analysis showed RPS was associated with significantly reduced: 1) NEC ≥ Stage II (30 studies, n = 77,018; OR: 0.60; 95% CI: 0.50, 0.73; P <0.00001, I2: 65%; LOE: Moderate), 2) LOS: (21 studies, n = 65,858; OR: 0.85; 95% CI: 0.74, 0.97; P = 0.02, I2: 74%; LOE: Low), and 3) all-cause mortality (27 non-RCTs, n = 70,977; OR: 0.77; 95% CI: 0.68, 0.88; P = 0.0001, I2: 49%; LOE: Low). Subgroups: 1) extremely low birth weight (ELBW: birth weight <1000 g) neonates: RPS was associated with significantly reduced NEC ≥ Stage II (4.5% compared with 7.9%). However, there was no difference in LOS and mortality. 2) Multistrain RPS was more effective than single strain. One study reported 3 nonfatal cases of probiotic sepsis. In summary, moderate- to low-quality evidence indicates that RPS was associated with significantly reduced NEC ≥ Stage II, LOS, and all-cause mortality in neonates <37 weeks of gestation and NEC ≥ Stage II in ELBW neonates.

Effect of single versus multistrain probiotic in extremely preterm infants: a randomised trial

“…[35][36][37] However, it is equally possible that TS probiotic was not superior in reducing TFF compared with SS, or its effect size was smaller than expected. It is important to note that other investigators have reported TFF of 11±3.6, 38 12 (9-16) 39 and 14 (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) 40 days in very preterm infants. Boscarino et al concluded that highenergy intake administered through the enteral route was positively correlated to cerebral growth, whereas energy intake via the parenteral route resulted in poorer cerebral growth.…”

“…The median TFF was comparable between the SS and TS groups (11)(12)(13)(14)(15)(16) vs 10 (IQR 8-16) days; HR 1.02, 95% CI 0.74 to 1.40; p=0.920).…”

“…Open access n=10 604 infants; I 2 =17%; LoE: low), 10 LOS (RR 0.89, 95% CI 0.82 to 0.97; 47 trials, n=9762 infants; I²=19%; LoE: moderate) 10 and duration of hospitalisation while facilitating enteral nutrition in preterm infants. [10][11][12] The mechanisms of benefits of probiotics include colonisation and normalisation of perturbed intestinal microbial communities, competitive exclusion of pathogens, bacteriocin production, increasing mucin production, modulating intestinal innate immunity and production of short-chain fatty acids (SCFAs), which strengthen the gut epithelial barrier and mediate anti-inflammatory, antimicrobial and immunomodulatory effects. 13 14 Probiotics, particularly bifidobacteria, specifically use human milk oligosaccharides and facilitate establishment of a bifidobacteria dominant gut ecosystem while inhibiting pathogenic micro-organisms.…”

“…Probiotics are live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host 9. Systematic reviews of randomised controlled trials (RCTs) and non-RCTs have shown that probiotics significantly reduce the risk of all-cause mortality ((relative risk (RR) 0.76, 95% CI 0.65 to 0.89; 51 trials, n=10 170 infants; I²=0%; level of evidence (LoE): moderate),10 NEC (RR: 0.54, 95% /CI 0.45 to 0.65; 54 RCTs, n=10 604 infants; I 2 =17%; LoE: low),10 LOS (RR 0.89, 95% CI 0.82 to 0.97; 47 trials, n=9762 infants; I²=19%; LoE: moderate)10 and duration of hospitalisation while facilitating enteral nutrition in preterm infants 10–12. The mechanisms of benefits of probiotics include colonisation and normalisation of perturbed intestinal microbial communities, competitive exclusion of pathogens, bacteriocin production, increasing mucin production, modulating intestinal innate immunity and production of short-chain fatty acids (SCFAs), which strengthen the gut epithelial barrier and mediate anti-inflammatory, antimicrobial and immunomodulatory effects 13 14.…”

Metabolic Phenotype and Microbiome of Infants Fed Formula Containing Lactobacillus paracasei Strain F-19

“…Probiotics are microorganisms thought to confer a health benefit when consumed through altering the composition of the intestinal microbiota. For premature infants, they are becoming more accepted as prophylaxis against necrotizing enterocolitis ( 15 , 16 ). Indeed, evidence has shown that provision of probiotics, such as Bifidobacterium animalis lactis, B. bifidum, B. infantis, Lactobacillus acidophilus, L. reuteri , and L. rhamnosus , in preterm and term infants as well as rhesus monkey infants has a significant impact on the microbial community structure ( 4 , 17 – 19 ).…”