The AAP issued guidance on probiotic use in the preterm infant last year in the form of what they call a “clinical report”, which I didn’t comment on at the time, I thought it might be a bit redundant as I have made my views pretty clear over the years. Unfortunately the AAP guidance was, in my view, based on a very limited and biased review of the available literature, comes up with recommendations which are really questionable, and continues to be challenged as more data accumulates.
Nothing in neonatology has been as extensively researched as probiotics. Somewhere over 12,000 preterm infants at risk of NEC have been randomized in trials so far. While it is true that trials are of extremely variable quality, from the poor to the exemplary, the overall quality of the evidence can be described as moderate to good. Of importance is that not a single trial has reported adverse outcomes as a result of probiotic use. Some have been null, some have been positive, but not one has been negative.
The variety of probiotic preparations used is another major problem. Which is why network meta-analyses have been performed (there are at least 4 published), examining the different probiotic formulations. The choices made regarding how the different formulations were grouped can be questioned, but the network meta-analysis which I think is the best quality (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), suggested that a combination of bifidobacterial species and a lactobacillus is optimal, and reduces the risk of NEC by about 50%. The other network meta-analyses have reached similar conclusions. As I previously mentioned, comparing studies that use a B infantis (otherwise known as B longum subsp. infantis) to other organisms would probably also conclude that B. infantis is the most important. Most of the studies using multi-organism combinations have included a B. infantis in the combined preparation, a network meta-analysis comparing treatment with B. infantis, either alone or in combination with other probiotics would therefore, I think, probably conclude that it was the most important of the organisms.
It seems to me that individuals and centres that have made the decision to not use probiotics seek to justify their decisions by invoking the “poor quality” of the evidence, whereas centres that have nevertheless introduced probiotics routinely see a fall in NEC incidence.
Even worse than the AAP statement is the press release that accompanied it, including a statement not found in the guidance document ” The most recent trials have not shown a reduction in NEC in those at highest risk”, which is just not true.
One of the problems with this literature which allows this type of interpretation is that many trials have not presented their data in a stratified fashion. In other words, the data have not been presented for babies above and below 1kg. Even though the mean birth weight of participants is about 1 kg; this allows the AAP to suggest that few babies under 1 kg have been studied, and efficacy in such babies is uncertain.
In reality, about half of the 12000 infants in the studies were <1kg, and there is nowhere any evidence of a differential effect based on body weight, indeed that would be weird. This would be the only intervention that I am aware of that works less well in higher risk babies than in lower risk infants.
In addition, the AAP statement suggests that centres that choose to use probiotics “should discuss the potential risks and benefits of this therapy with parents and should strongly consider a formalized informed consent process”, I will never be someone to suggest that we should not discuss the potential risks and benefits of a therapy with parents, but what risks does the AAP want us to discuss? Among the huge numbers of babies in RCTs, there were no reported risks, indeed an evidence-based discussion of the risks would go something like: “there are a few reported cases of sepsis with probiotic organisms outside of the trials, and there is no sign in any of the trials that the risk of receiving probiotics is more than the risk of not receiving them, all the evidence shows that the risk benefit of probiotic administration is heavily on the side of benefit”.
More importantly, why don’t the AAP suggest an informed consent process for those centres who don’t give probiotics? Surely, the evidence, which shows that giving probiotics containing B. infantis, or a mixture of Bifidobacteria and Lactobacilli, has benefits and minimal risks, should be discussed with every parent in every NICU, not just in those who give them, but even more importantly, in those who don’t. Shouldn’t every parent have the opportunity to ask for a treatment which has only shown benefit in RCTs?
I’m trying to think of a parallel, but I think that all other low risk procedures and moderate risk procedures are universally available, I don’t think there are NICUs that have decided to never give surfactant, or antibiotics, or CPAP. So the only partial parallel I can think of is for extremely high risk procedures, such as ECMO. If you are looking after a sick full term baby with meconium aspiration who reaches ECMO criteria and you are in a centre that doesn’t offer ECMO, would the AAP consider it OK to not discuss transfer to an ECMO centre? That only centres offering ECMO discuss the risks and benefits, and the others should just pretend that ECMO doesn’t exist?
An decision to cannulate for ECMO is of course extremely high risk, and warrants extensive discussion with parents, and if you are in a non-ECMO centre, then the discussion should also involve the risks of the transport, but if it is a reasonable alternative for the individual baby, then that discussion should always take place.
I am not sure if many centres really use a “formalized consent process” for giving antibiotics, or surfactant? Interventions for which the risk/benefit is often much more questionable than for probiotics.
To put it bluntly, the current AAP advice is that parents in centres that do not currently offer probiotic prophylaxis for NEC should have the evidence hidden from them, and there is no obligation for them to be informed. In 2022 that is unlikely to be a successful policy, I am sure that many parents in the USA search the interwebs when their baby is in the NICU, and especially those whose baby develops NEC are likely to find the NEC society web site, whose educational materials clearly state :
“There is also good evidence that giving premature babies probiotics reduces their risk of NEC and increases their chance of survival. Neither human milk nor probiotics can eliminate the risks of NEC”.
“Are there any risks of getting probiotics?
There are risks and benefits to every treatment. The benefits of probiotics include maintenance of healthy bacteria in the intestine. This is believed to help prevent NEC. In rare situations, probiotic bacteria can get into the blood and cause infections. If babies develop an infection in the blood with the probiotic bacteria, they are given an antibiotic to kill the probiotic bacteria. When this has happened, the infections have been responsive to treatment. Based on the literature, it appears that the benefits of probiotic administration outweigh the potential risks.”
A new publication of a before and after study in an NICU in Portland Oregon (Tobias J, et al. Bifidobacteriumlongum subsp. infantis EVC001 Administration Is Associated with a Significant Reduction in the Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants. J Pediatr. 2022) showed a substantial decrease in NEC after introduction of routine B Infantis supplementation, and an elimination of NEC deaths. As I have previously mentioned, I think it is scandalous that Evivo is being aggressively marketed without the kind of RCT evidence that would be needed if it were a medication, there really is no scientific justification for this. It would not be difficult to perform the sort of trial that is needed to prove that Evivo truly is effective, and also is more effective than alternatives. I believe that it has the manufacturing standards that are required, we just need proof of efficacy from an RCT.
In an excellent editorial accompanying that publication Mark Underwood notes that the AAP statement does not suggest a “formalized consent process” for other interventions that reduce NEC, unpasteurized maternal milk administration and banked human milk use, even though the small risks from those interventions are probably greater than the risks of probiotics. Of course, the risk/benefit ratio of fresh maternal milk, and supplementation with banked donor milk, are clearly in favour of their use, but that is also the case for probiotics.
I think the AAP missed an opportunity to advocate for the development of probiotic preparations that are of sufficiently high quality, with stringent quality control and safety data, they missed the opportunity to advocate for comparative trials, with individual or cluster randomization. There are still many unknowns with probiotics, and trials comparing different strains, and different combinations could have a huge impact on preventing this atrocious disease. I think that trials comparing a B, Infantis alone, to a B. Infantis in combination with a Lactobacillus, and perhaps to a B. Infantis and oligosaccharide combination (preferably with DSLNT), would have a chance of improving care of very preterm infants and reducing the terrible consequences of NEC.
May is NEC awareness month, and May 17th is NEC awareness day. With those dates in mind, consider supporting the NEC Society, an organisation which involves parents and professionals, with the overall goal to create a world without NEC. A worthy goal indeed.
Dear Keith, I agree fully and totally on what you wrote. Best wishes !