Probiotics, Prebiotics, Lactoferrin, and Combination Products for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis

Abstract

Importance: Modulation of intestinal microbiome by administering probiotics, prebiotics, or both may prevent morbidity and mortality in premature infants.

Objective: To assess the comparative effectiveness of alternative prophylactic strategies through a network meta-analysis (NMA) of randomized clinical trials.

Data sources: MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, and Google Scholar from inception until May 10, 2023.

Study selection: Eligible trials tested probiotics, prebiotics, lactoferrin, and combination products for prevention of morbidity or mortality in preterm infants.

Data extraction and synthesis: A frequentist random-effects model was used for the NMA, and the certainty of evidence and inferences regarding relative effectiveness were assessed using the GRADE approach.

Main outcomes and measures: All-cause mortality, severe necrotizing enterocolitis, culture-proven sepsis, feeding intolerance, time to reach full enteral feeding, and duration of hospitalization.

Results: A total of 106 trials involving 25 840 preterm infants were included. Only multiple-strain probiotics were associated with reduced all-cause mortality compared with placebo (risk ratio [RR], 0.69; 95% CI, 0.56 to 0.86; risk difference [RD], -1.7%; 95% CI, -2.4% to -0.8%). Multiple-strain probiotics alone (vs placebo: RR, 0.38; 95% CI, 0.30 to 0.50; RD, -3.7%; 95% CI, -4.1% to -2.9%) or in combination with oligosaccharides (vs placebo: RR, 0.13; 95% CI, 0.05 to 0.37; RD, -5.1%; 95% CI, -5.6% to -3.7%) were among the most effective interventions reducing severe necrotizing enterocolitis. Single-strain probiotics in combination with lactoferrin (vs placebo RR, 0.33; 95% CI, 0.14 to 0.78; RD, -10.7%; 95% CI, -13.7% to -3.5%) were the most effective intervention for reducing sepsis. Multiple-strain probiotics alone (RR, 0.61; 95% CI, 0.46 to 0.80; RD, -10.0%; 95% CI, -13.9% to -5.1%) or in combination with oligosaccharides (RR, 0.45; 95% CI, 0.29 to 0.67; RD, -14.1%; 95% CI, -18.3% to -8.5%) and single-strain probiotics (RR, 0.61; 95% CI, 0.51 to 0.72; RD, -10.0%; 95% CI, -12.6% to -7.2%) proved of best effectiveness in reduction of feeding intolerance vs placebo. Single-strain probiotics (MD, -1.94 days; 95% CI, -2.96 to -0.92) and multistrain probiotics (MD, -2.03 days; 95% CI, -3.04 to -1.02) proved the most effective in reducing the time to reach full enteral feeding compared with placebo. Only single-strain and multistrain probiotics were associated with greater effectiveness compared with placebo in reducing duration of hospitalization (MD, -3.31 days; 95% CI, -5.05 to -1.58; and MD, -2.20 days; 95% CI, -4.08 to -0.31, respectively).

Conclusions and relevance: In this systematic review and NMA, moderate- to high-certainty evidence demonstrated an association between multistrain probiotics and reduction in all-cause mortality; these interventions were also associated with the best effectiveness for other key outcomes. Combination products, including single- and multiple-strain probiotics combined with prebiotics or lactoferrin, were associated with the largest reduction in morbidity and mortality.

Figure 1.. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram for Study Selection

Figure 2.. Network of Eligible Comparisons

The size of the node corresponds to the number of infants randomized to that intervention. The interventions directly compared are linked with a line; the thickness of the line corresponds to the number of trials that assessed the comparison. LF indicates lactoferrin; MultiPrb, multiple-strain probiotics; OLGS, oligosaccharides (human milk oligosaccharides, fructo-oligosaccharides, and/or galacto-oligosaccharides); SinglePrb, single-strain probiotics.

Figure 3.. Network Meta-Analysis Results Sorted Based on Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Certainty of Evidence and Effect Estimates for the Comparisons of Active Interventions vs Placebo

Numbers in bold indicate statistically significant results. LF indicates lactoferrin; MD, mean difference; MultiPrb, multiple-strain probiotics; NA, not available; NEC, necrotizing enterocolitis; OLGS, oligosaccharides (human milk oligosaccharides, fructo-oligosaccharides, and/or galacto-oligosaccharides); RR, risk ratio; SinglePrb, single-strain probiotics.

Figure 4.. Network Meta-Analysis Results for All-Cause Mortality (Bottom-Left Half) and Necrotizing Enterocolitis Stage 2 or 3 (Top-Right Half)

Results are risk ratio (95% CI) from the network meta-analysis. For each column compared with the row, a risk ratio less than 1 means the intervention in the top-left blue cell is better (a risk ratio >1 favors the intervention in the column). Numbers in bold indicate statistically significant results. Each result cell’s color represents the certainty of the evidence for the pairwise comparison. LF indicates lactoferrin; MultiPrb, multiple-strain probiotics; OLGS, oligosaccharides (human milk oligosaccharides, fructo-oligosaccharides, and/or galacto-oligosaccharides); SinglePrb, single-strain probiotics.