Probiotics for the prevention of mortality and sepsis in preterm very low birth weight neonates from low- and middle-income countries: a Bayesian network meta-analysis

Abstract

Background: Probiotics have been shown to reduce the risk of mortality and necrotizing enterocolitis (NEC) in very low birth weight (VLBW) neonates. The probiotic species with the maximal benefits in neonates from low- and middle-income countries are unknown.

Objective: To identify the strain of probiotics with the maximum benefit in preventing neonatal mortality, sepsis, and NEC using the Bayesian network meta-analysis.

Search methods: We searched Medline via PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). We also hand-searched reference lists of previous systematic reviews to identify eligible studies.

Selection criteria: Randomized controlled trials (RCTs) from LMICs comparing enteral supplementation of one or more probiotics with another probiotic species or placebo were included.

Data collection and analysis: Two authors screened the studies, extracted the data, and examined the risk of bias using the Cochrane risk of bias 2 (RoB 2) tools. Bayesian network meta-analysis was performed using the "BUGSnet" package in R and RStudio (version 1.4.1103). The confidence in the findings was assessed using the Confidence in Network Meta-analysis (CINeMA) web application.

Results: Twenty-nine RCTs enrolling 4,906 neonates and evaluating 24 probiotics were included. Only 11 (38%) studies had a low risk of bias. All the studies compared the probiotics with a placebo; none had a head-to-head comparison of different probiotic species. Also, only one study each had evaluated most probiotic regimens. When compared to placebo, the combination of B longum, B bifidum, B infantis, and L acidophilus may reduce the risk of mortality (relative risk [RR] 0.26; 95% credible interval [CrI] 0.07 to 0.72), sepsis (RR 0.47; 95% CrI 0.25 to 0.83), and NEC (RR 0.31; 95% CrI 0.10 to 0.78) but the evidence is very uncertain. There is low certainty evidence that the single probiotic species, B lactis, could reduce the risk of mortality (RR 0.21; 0.05 to 0.66) and NEC (RR 0.09; 0.01 to 0.32).

Conclusion: Given the low to very low certainty of evidence for the efficacy of the two probiotics found to reduce mortality and necrotizing enterocolitis, no firm conclusions can be made on the optimal probiotics for use in preterm neonates in low- and middle-income countries.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022353242, identifier: CRD42022353242.

Keywords: enterocolitis; necrotizing; neonatal mortality; neonatal sepsis; neonate; network meta-analysis; probiotics; very low birth weight.

Figure 1

Flow chart of search results (adapted from PRISMA 2009 flow diagram).

Figure 2

(A) Network plot depicting the studies included for mortality. (B) Network plot depicting the studies included for sepsis. The nodes represent the interventions evaluated in the network. The size of the nodes is proportional to the number of patients assigned to the intervention, while the thickness of the lines connecting the nodes is proportional to the number of pairwise trials that evaluated the interventions (shown as numbers along the lines). Refer to Figure 3 for the expansion of the abbreviations.

Figure 3

(A) Forest plots depicting the relative risks of different probiotic species compared with placebo for mortality. (B) Forest plots depicting the relative risks of different probiotic species compared with placebo for sepsis. Sab, Saccharomyces boulardii; L spo, Lactobacillus sporogenes; L reu, L reuteri; BrLca, B breve+L casei; BLSa, B bifidum+L acidophilus+Sa boulardii; BloLr, B longum+L rhamnosus; BLaE; L acidophilus+ b infantis+ bacillus cereus+ E fecalis; Blac, B lactis; BL2Sa, B longum+L helveticus+L rhamnosus+Sa boulardii; BL2aSa, B longum+L acidophilus+L rhamnosus+Sa boulardii; BL2aS, B spp+L acidophilus+S thermophilus+L delbrueckii; BinL4S, B infantis+L rhamnosus+L casei+L plantarum+L acidophilus+S thermophilus;BiLac, B bifidum+L acidophilus; Bacl, Ba clausii; B3L4, B bifidum+ B longum+B infantis+L rhamnosus+L paracasei+L casei+L acidophilus+L lactis; B3L, B longum+B bifidum+B lactis+L acidophilus; B3iL, B longum+B bifidum+B infantis+L acidophilus; B2L4S, B longum+ B breve+L acidophilus+L rhamnosus+L bulgaricus+L casei+S thermophiles.

Figure 4

(A) SUCRA plot of the network meta-analysis for mortality. (B) SUCRA plot of the network meta-analysis for sepsis. Refer to Figure 3 for the expansion of the abbreviations.