In a recent study published in the European Journal of Clinical Nutrition, a group of researchers assessed the strain-specific effects of Lactobacillus rhamnosus GG (LGG) in preterm infants through a systematic review and meta-analysis of randomized controlled trials (RCTs) and non-RCTs.
Study: Lactobacillus rhamnosus GG as a probiotic for preterm infants: a strain specific systematic review and meta-analysis. Image Credit: Ratchat/Shutterstock.com
Background
Probiotics, live microorganisms providing health benefits, have been shown to reduce the risk of Necrotizing Enterocolitis (NEC) (a severe intestinal disease in preterm infants) ≥ Stage II, all-cause mortality, late-onset sepsis (LOS), and time to full feeds (TFF) among preterm very low birth weight (VLBW) infants. However, challenges remain regarding the optimal strain, duration, dose, and safety.
The effectiveness of probiotics is often strain-specific, necessitating detailed strain-specific data for guiding clinical practice and research. LGG is widely used for gastrointestinal infection prevention, especially in pediatric populations.
Further research is needed to determine the optimal strain, duration, dose, and safety of probiotics for preterm infants, as the effects are strain-specific and current data show significant heterogeneity.
About the study
The present study adhered to Cochrane methodology and preferred reporting items for systematic reviews (PRISMA 2020) guidelines. It included RCTs and non-RCTs published up to December 2023 involving preterm infants born earlier than 37 weeks gestation or weighing under 2,500 g.
The intervention was enteral administration of LGG ATCC 53103 alone or with other probiotics, starting within the first ten days of life for at least seven days, compared to a placebo or control.
Primary outcomes included NEC ≥ Stage II, LOS, mortality, TFF, and hospitalization duration, while secondary outcomes covered birth weight regain, feed intolerance, Candida colonization, and invasive candidiasis.
The search spanned the Cochrane Central Register, Excerpta Medica database (EMBASE), PubMed, and Cumulative Index of Nursing and Allied Health Literature (CINAHL) databases, with no restrictions on design or language.
Additional studies were identified through references, grey literature and Google Scholar. Three reviewers searched and assessed study quality using the grading of recommendations, assessment, development, and evaluation (GRADE) system.
Abstracts were reviewed for eligibility, with full-text assessments using predefined criteria. Data extraction and risk of bias assessment followed Cochrane Neonatal Review Group guidelines.
Meta-analysis was performed using Review Manager 5.3, expressing effect sizes as risk ratios (RR) with 95% confidence intervals (CI).
Statistical heterogeneity was evaluated with the χ2 test and I2 statistic. Trial sequential analysis and subgroup analyses were conducted, and findings were summarized according to GRADE guidelines.
Study results
The literature search retrieved 1,435 potentially relevant citations. After excluding 995 duplicates and 331 studies that did not meet inclusion criteria, 24 RCTs and eight non-RCTs were included. 11 RCTs studied single-strain LGG, while the remaining 13 used multi-strain probiotics.
In RCTs using single-strain LGG, probiotic supplementation continued until discharge in six studies and for a specified duration in five. 8 RCTs focused on preterm infants under 34 weeks, while three included babies born between 34-37 weeks gestation.
Non-RCTs used single-strain LGG, with supplementation continuing until discharge in two studies and for a specified period in one, all involving infants born before 32 weeks gestation.
The risk of bias (ROB) assessment showed that ten of the eleven single-strain LGG RCTs had 8 for allocation concealment, low ROB for random sequence generation, and 8 for intervention blinding.
7 multi-strain probiotic RCTs had low ROB for random sequence generation, allocation concealment, and intervention blinding. Non-RCTs were assessed using the Newcastle Ottawa scale, with seven studies scoring eight and one scoring seven.
Meta-analysis of single-strain LGG RCTs showed a significantly lower risk of NEC ≥ Stage II [RR:0.50 (95% CI: 0.26, 0.93), P = 0.03] and no significant difference in LOS, all-cause mortality, TFF, or duration of hospital stay.
The trial sequential analysis (TSA) for NEC from these RCTs indicated a required information size of 1,500, while the current number was 851. For a risk reduction of 30%, the Diversity Adjusted Required Information Size (DARIS) would be 4,290.
Meta-analysis of non-RCTs found no significant effect of single-strain LGG on LOS, NEC, or mortality. Multi-strain probiotic RCTs showed a significantly lower risk of NEC ≥ Stage II [RR:0.38 (95% CI: 0.24, 0.62), P < 0.0001], decreased mortality [RR 0.31 (95% CI: 0.17, 0.54), P < 0.0001], reduced TFF, and shorter hospital stays. Non-RCTs of multi-strain probiotics found no significant effect on NEC, LOS, or mortality.
Sensitivity analysis showed a beneficial effect of single-strain LGG on NEC in studies with low ROB and probiotic supplementation until discharge.
There was no significant effect on mortality, LOS, TFF, or hospital duration. Publication bias was deemed unlikely, and no cases of probiotic sepsis were reported in the included studies.
Conclusions
The systematic review of RCTs found that single-strain LGG significantly reduces NEC in preterm infants but does not impact other outcomes. Multi-strain probiotics containing LGG showed NEC, mortality, LOS, and hospital stay benefits.
Non-RCTs did not show significant effects for single-strain LGG, highlighting discrepancies. The review underscores the need for robust, adequately powered RCTs to confirm these findings.
Sensitivity analysis indicated benefits for NEC with continuous LGG supplementation until discharge.
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