Review for 10.1186/s12876-025-03788-0 (2025)

Title: The effectiveness of treatment with probiotics in preventing necrotizing enterocolitis
and related mortality: Results from an umbrella meta-analysis on meta-analyses of randomized
controlled trials
Version: 2 Date: 22 Feb 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-While heterogeneity is assessed statistically, the variations in study populations, probiotic
strains, dosages, and even treatment protocols might still lead to significant differences between
the studies. These variations could complicate the interpretation of the results.
-While the article highlights several proposed mechanisms for how probiotics may work in the
gastrointestinal tract (e.g., restoring microbiota, modulating immune responses), the review does
not provide detailed insights into how specific probiotic strains function. More information on
the exact strains used in the studies and their specific effects would enhance the understanding
of the intervention’s underlying mechanisms.
-The primary focus is on NEC prevention and mortality, but there is little discussion about
the long-term effects of probiotic supplementation. Understanding how probiotics influence the
development and overall health of preterm infants beyond their immediate impact on NEC is
essential for guiding long-term neonatal care.
-The exclusion of non-meta-analytic studies (e.g., individual RCTs or observational studies)
might limit the overall scope of the review. While meta-analyses provide strong evidence,
including high-quality individual studies could broaden the analysis and provide more direct
insights.
-While publication bias is assessed using funnel plots and statistical tests, publication bias
remains a common issue in systematic reviews and meta-analyses. Negative or null results are
less likely to be published, which could affect the balance and generalizability of the findings.
-One of the key limitations mentioned is the absence of consistent data on the dose and duration
of probiotic supplementation. This is a critical factor, as optimal dosing and duration may vary,
and without this data, the clinical applicability of the findings remains uncertain. Subgroup
analyses based on these factors could have provided more tailored recommendations.
-While the review identifies that multi-strain probiotics work better for infants with a birth
weight of 1500–2500 grams and those over 37 weeks gestational age, this finding is based on
subgroup analyses with limited data. More detailed, stratified analyses would be helpful to fully
understand the impact of probiotics on various subgroups, including very low birth weight or
extremely preterm infants.
-While the mechanisms are discussed, more information on how specific strains (such as
Lactobacillus or Bifidobacterium) may interact with the infant microbiome and immune system
could add depth to the discussion. A deeper understanding of strain-specific benefits would
guide the clinical choice of probiotics.
-The study does not fully explore clinical factors such as comorbidities or the use of concurrent
treatments (e.g., antibiotics or ventilator support) that might influence the effectiveness of
probiotics in preventing NEC. These factors could significantly alter the outcomes of probiotic
supplementation.