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.
The results are summarized in this table.
The meaning of the colours in the table is as follows
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!
Thanks for the review of this. Are you familiar with the Tri-Blend formulation from Abbott? It does not contain lactobacillus but does have two bifidobacterium and s. Thermophilus. Given the lack of availability in the US of a product with a combination of lactobacillus and bifidobacterium, we are considering it for our unit.
I do not know that product specifically, but I would think that Abbott would probably have good enough manufacturing standards to have confidence in their product. I believe that the EVIVO company are currently suing Abbott with regard to this very formulation, I can’t understand what they are claiming that Abbott is doing wrong.
Given the data that are available, I think it is likely that B infantis is the most important (also called B longum subsp infantis). Mark Underwood has published about this (and although he is from UC Davis he doesn’t appear to be directly involved with EVIVO). However, I don’t think there is a NEC trial using just B infantis. There is a recent study using their product in term babies, that Mark was involved in (Henrick BM, et al. Colonization by B. infantis EVC001 modulates enteric inflammation in exclusively breastfed infants. Pediatr Res. 2019;86(6):749-57, funded and mostly written by EVIVO employees), but not as far as I am aware in preterm infants.
The Abbott product appears to be similar or identical to the one used in PROPREMS in Australia, this came out in the network meta-analysis as being effective for NEC with an Odds Ratio similar to their best choice (OR 0.38, 0.19-0.75, in the table it is referred to as “Bifidobacterium spp and Streptococcus salivarius subsp thermophilus”), however, I think that is the only trial that has used that particular mix, so the confidence intervals are wider. As the study was in Australia mortality rates were much lower than in some other trials, so the reduction in all-cause mortality was not as striking (OR 0.84, 0.5-1.4). I think it is a good choice given availability and confidence issues with other products.
Perhaps parents will help change something, the same way they advocate for other interventions. This is how we started using probiotics years ago, very early in fact, after a mom demanded we use it. Then other parents asked for it, then, we started a study (published). I guess we need a mom/dad in neonatology who asks, after an episode of NEC, why her/his baby was not given probiotics. Or a parent helps develop a QI in a hospital. The CPS should definately say something.
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