Necrotizing enterocolitis (NEC) and sepsis are major causes of mortality among preterm infants.1,2  Microbial dysbiosis or imbalance in the preterm gut may predispose to NEC, and optimizing the gut microbiome with probiotics is a promising strategy to prevent NEC.3  Multiple previous meta-analyses have reported that enteral supplementation with probiotics, compared to placebo, reduces the risks of NEC, sepsis, and mortality.4  Prebiotics, which support the growth or activity of beneficial bacteria, may also reduce the risks of sepsis and mortality.5  However, there is uncertainty regarding the relative efficacy of different types of probiotics, prebiotics, or synbiotics (combinations of the 2) in preventing morbidity or mortality in preterm infants.

In this issue of Pediatrics, Chi et al6  present a systematic review and network meta-analysis (NMA) evaluating the effects of probiotics and synbiotics in preterm infants.

The protocol for the systematic review was preregistered, and trials in which authors evaluated both probiotics and synbiotics in preterm infants were searched. The primary outcomes were all-cause mortality and NEC. An NMA was performed to compare the relative efficacy of the various supplements and included 45 randomized trials with 12 320 participants that evaluated 14 different interventions or placebo. The NMA revealed that Lactobacillus plus prebiotic, Bifidobacterium plus prebiotic, and Bifidobacterium plus Lactobacillus were each associated with a lower risk of mortality and NEC compared to placebo. In addition, Lactobacillus plus prebiotic, compared to placebo, was associated with a lower risk of sepsis. When ranked by using the surface under the cumulative ranking curve (SUCRA), Bifidobacterium plus prebiotic had the highest probability of having the lowest rate of mortality (SUCRA 84%) and Lactobacillus plus prebiotic had the highest probability of having the lowest rate of NEC (SUCRA 96%).

Because effects of probiotics may vary by strain and be influenced by prebiotics,7  this systematic review and meta-analysis provides additional data regarding the relative efficacy of supplementation of probiotics or synbiotics. Van den Akker et al,8  in a previous NMA focused on strain-specific effects of probiotics, evaluated 51 trials with 11 231 infants. In this review, 25 different strains were evaluated, of which 3 revealed significant reductions in mortality, 7 reductions in NEC, and 2 reductions in late-onset sepsis. However, assessment of treatment effects of individual strains was limited by imprecision in effect estimates because of small sample sizes of the included trials. This previous NMA served as the basis of a conditional recommendation from the European Society for Pediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics, on the basis of low certainty of evidence, for 2 strains to prevent NEC: Lactobacillus rhamnosus GG ATCC53103 or Bifidobacterium infantis Bb-02, Bifidobacterium lactis Bb-12 and Streptococcus thermophilus TH-4.9 

In their NMA, Chi et al6  build on these findings by providing additional information on prebiotics in combination with probiotics, with findings suggesting that the synbiotic combinations may have greater treatment efficacy than probiotic supplementation alone. The impact of human milk feeding, which contains prebiotics (eg, oligosaccharides), in combination with probiotics or synbiotics was not evaluated in this review. However, NMA and SUCRA rankings have limitations that should be considered in interpretation of the findings, as noted by Mbuagbaw et al.10  SUCRA rankings need to the viewed with the quality or certainty of evidence (eg, SUCRA rankings may be misleading if the included studies have high risk of bias) and may be outcome dependent (more effective in one outcome but less effective or harmful in another). In addition, SUCRA rankings do not consider the magnitude of differences in effects between treatments or the possibility of chance findings. Therefore, the rankings of various treatments in the study by Chi et al6  should be interpreted with caution. Also, there are fewer data on the efficacy of probiotics and synbiotics in extremely preterm infants who have the highest risk of NEC, mortality, and sepsis. In addition to relative efficacy, additional considerations regarding choice of probiotic and synbiotic products include quality, availability, preparation, and costs.

In their NMA, Chi et al6  provide additional evidence that supports the potential benefits of probiotic use in preterm infants by clinicians to reduce the risks of NEC, death, and late-onset sepsis. The findings also highlight the need for additional studies by researchers to determine if synbiotics are superior to probiotics for use in preterm infants and how human milk intake, which is a source of prebiotics, may influence the treatment effects of different probiotics strains.

Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.

FUNDING: Dr Pammi is funded by National Institutes of Health grants R03HD098482 and R21HD091718 not related to this commentary. Dr Patel is funded by National Institutes of Health grants UG1HD027851 and K23HL128942, which involve research focused on necrotizing enterocolitis but not related to this commentary.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2020-0706.

NEC

necrotizing enterocolitis

NMA

network meta-analysis

SUCRA

surface under the cumulative ranking curve

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Patel serves on the data safety monitoring committee of the Connection Study, conducted by Infant Bacterial Therapeutics and Premier Research; Dr Pammi has indicated he has no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.