The American Gastroenterological Association has recently published its guidance about probiotics for various conditions. They found little evidence of benefit for most indications with the probable exception of preventing antibiotic-associated diarrhoea. The 8th indication that they reviewed was the prevention of NEC. Their conclusion after robust evidence review was
In this vulnerable population of premature infants … these data strongly suggest that probiotics may protect from mortality and do not increase rates of sepsis.
The full systematic review and network meta-analysis has been published. (Morgan RL, et al. Probiotics Reduce Mortality and Morbidity in Preterm, Low-Birth-Weight Infants: A Systematic Review and Network Meta-analysis of Randomized Trials. Gastroenterology. 2020;159(2):467-80). They found 63 trials which included a total of over 15,000 infants.
The published article does not have one of those weird network plots, and I am sure you would miss it, so here is a plot from the supplemental data
B. adolescentis: Bifidobacterium adolescentis; B. & B.: Bifidobacterium animalis subsp. lactis & Bifidobacterium longum subsp. longum; Bac. coagulans: Bacillus coagulans; Bac & En.: Bacillus spp. & Enterococcus spp.; B. & Strp.: Bifidobacterium spp. & Streptococcus salivarius subsp. thermophilus; B. bifidum: Bifidobacterium bifidum; B. lactis: Bifidobacterium animalis subsp. lactis; B. longum: Bifidobacterium longum subsp. longum; B. breve: Bifidobacterium breve; B. clausii: Bacillus clausii; L. acidophilus: Lactobacillus acidophilus; L. & B.: Lactobacillus spp. & Bifidobacterium spp.; L. & B. & En.: Lactobacillus spp. & Bifidobacterium spp. & Enterococcus spp.; L. reuteri: Lactobacillus reuteri; L. & B. & Sac.: Lactobacillus spp. & Bifidobacterium spp. & Saccharomyces boulardii; L. & B. & Strp.: Lactobacillus spp. & Bifidobacterium spp. & S.
salivarius subsp. thermophilus; L. rhamnosus: Lactobacillus rhamnosus; S. boulardii: Saccharomyces boulardi.
Compared with placebo, a combination of 1 or more Lactobacillus species and 1 or more Bifidobacterium species was the only intervention with moderate- or high-quality evidence of reduced mortality (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.39–0.80).
Among interventions with moderate- or high-quality evidence for efficacy compared with placebo, combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp, significantly reduced severe NEC (OR, 0.35 [95% CI, 0.20–0.59].
Unlike some other SRs with meta-analysis, they did not show a reduction in late-onset sepsis. They also did not show any significant incidence of invasive infection with the probiotic organisms.
One thing I have difficulty understanding is the lack of clear guidance from either the American Academy of Pediatrics or the Canadian Paediatric Society regarding probiotic use in the preterm. Anything else that had been studied in 63 RCTs with over 15000 babies randomized showing a reduction in mortality, and a large reduction in serious NEC would surely by now have been the subject of a neonatal-specific position statement. The AAP does have a statement from the
I think that this new systematic review and network meta-analysis is clear enough. All at-risk babies should be receiving probiotics, and they should be receiving a mixture which includes 1 or more Lactobacillus species and 1 or more Bifidobacterium species. I think that clinicians need guidance on how to find a reliable safe source.
In Canada, we are fortunate that there is some regulation of such products by Health Canada, who have awarded an NPN to some probiotic products. A Natural Product Number is evidence of quality control and Good Manufacturing Practice standards, and that there is reason to believe that what is in the bottle is actually what it says on the label.
I have heard that EVIVO is being marketed very aggressively to hospitals in the USA, as a potential prophylactic agent against NEC. It is from an enterprise started by researchers from UCDavis, I believe, and as far as I can see they have very high manufacturing standards. However, single strain B. infantis, which is what EVIVO is, has not been studied in any RCT in the preterm to my knowledge. Many of the combination products, shown to be the most effective in this new network meta-analysis, did contain a B. infantis; but not all of them. I think it would be great if EVIVO performed an RCT against one of the other combination products shown to be effective. Indeed the network meta-analysis that I quote includes that as its final recommendation; “further research is needed”; how innovative a recommendation!