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#189 - 🦠 Probiotics Mini Series - A review of the evidence (ft Dr. Jonathan Blau)





Hello Friends 👋

We are delighted to unveil our latest mini-series on The Incubator Podcast, focusing on the pivotal role of probiotics in the Neonatal Intensive Care Unit (NICU). Amidst growing conversations about the benefits of probiotics in neonatal care, we have convened three leading experts to examine the evidence at hand, explore strategies for Necrotizing Enterocolitis (NEC) prevention, and discuss a host of other relevant topics. Hosted by Ben and Daphna, this four-part series promises to offer deep insights and enriching discussions, making it a must-listen for healthcare professionals and anyone interested in the advancements in NICU care. Join us on this enlightening journey, only on The Incubator Podcast.


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Short bio: Dr. Jonathan Blau is Director of Neonatology at Staten Island University Hospital in the Northwell Health System and Associate Professor of Pediatrics at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. His academic interests include the neonatal microbiome, antimicrobial stewardship, NEC and preterm nutrition after NICU discharge. After receiving his MD from the Stony Brook School of Medicine, he completed a pediatrics residency at the NYU School of Medicine and neonatology fellowship at New York Medical College. He recently completed a five-year term as President of the New York Perinatal Society and has been voted "Northwell Teacher of the Year" for the Northwell Health System in New York. Dr. Blau is an active member of the Society for Pediatric Research.


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The articles covered on today’s episode of the podcast can be found here 👇

Rao SC, Athalye-Jape GK, Deshpande GC, Simmer KN, Patole SK.Pediatrics. 2016 Mar;137(3):e20153684. doi: 10.1542/peds.2015-3684. Epub 2016 Feb 12.PMID: 26908700 Review.

 

Dermyshi E, Wang Y, Yan C, Hong W, Qiu G, Gong X, Zhang T.Neonatology. 2017;112(1):9-23. doi: 10.1159/000454668. Epub 2017 Feb 15.PMID: 28196365 Free article. Review.

 

Patel RM, Underwood MA.Semin Pediatr Surg. 2018 Feb;27(1):39-46. doi: 10.1053/j.sempedsurg.2017.11.008. Epub 2017 Nov 6.PMID: 29275816 Free PMC article. Review.

 

van den Akker CHP, van Goudoever JB, Shamir R, Domellöf M, Embleton ND, Hojsak I, Lapillonne A, Mihatsch WA, Berni Canani R, Bronsky J, Campoy C, Fewtrell MS, Fidler Mis N, Guarino A, Hulst JM, Indrio F, Kolaček S, Orel R, Vandenplas Y, Weizman Z, Szajewska H.J Pediatr Gastroenterol Nutr. 2020 May;70(5):664-680. doi: 10.1097/MPG.0000000000002655.PMID: 32332478

 

Poindexter B; COMMITTEE ON FETUS AND NEWBORN.Pediatrics. 2021 Jun;147(6):e2021051485. doi: 10.1542/peds.2021-051485. Epub 2021 May 24.PMID: 34031231

 

Chiruvolu A, Hendrikson H, Hanson R, Reedy A, Reis J, Desai S, Suterwala M.J Perinatol. 2023 May;43(5):635-641. doi: 10.1038/s41372-023-01657-w. Epub 2023 Mar 30.PMID: 36997802

 

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The transcript of today's episode can be found below 👇


Ben Courchia MD (00:00.79)

Hello everybody. Welcome back to the incubator podcast. We are back with a new series. This time around we are focusing on probiotics and in this first episode, we have the pleasure of having on with us, Dr. Jonathan Blau. Before we introduce Dr. Blau, Daphna how are you this fine morning?

 

Daphna Yasova Barbeau, MD (she/her) (00:24.536)

I'm doing quite well, I'm excited to be on. And we've been looking forward to talking to Dr. Blau and learning more about all of the work that has gone in to the study of probiotics in the NICU.

 

Ben Courchia MD (00:40.268)

Dr. Jonathan Blau, welcome and thank you for being on the show with us.

 

Jonathan Blau (00:45.525)

Thank you, Ben. Thank you, Daphna. It's a pleasure to be with you today and it's really an honor to be on the Incubator podcast. Thank you.

 

Ben Courchia MD (00:53.63)

Ah, the honor is mutual. I'm going to give a brief bio for people who may not be familiar with your work. You are the director of neonatology at Staten Island University Hospital in the Northwell Health System in New York, and you're an associate professor of pediatrics at the Donald and Barbara Zucker School of Medicine at Hofstra slash Northwell. Your academic interests include the neonatal microbiome,

 

antimicrobial stewardship, NEC, and preterm nutrition after NICU discharge. You recently completed a five-year term as the president of the New York Perinatal Society, and you've received multiple awards, including a Northwell Teacher of the Year for the Northwell Health System in New York, which is not a small feat because the people who practice in New York, they know how wide the Northwell Health System is. So the pool is strong. So kudos for that. And...

 

Jonathan Blau (01:47.259)

Thank you.

 

Ben Courchia MD (01:48.81)

Yeah, and you're a member of the society, an active member of the Society for Pediatric Research. Jonathan, today what we would like to start with really is to try to get a sense of what does the evidence look like for probiotics? It seems like there's a lot of stuff that has been published for some time, and I think for all of us, we're thinking, well, if I remember correctly, when I'm looking at mid-analyses and stuff like that, it seems like

 

Probiotics, good for the babies, preterm, at risk of NEC. But can you try to give us a little bit of a historical perspective on when did the first paper come? How old is the evidence that we're working with, and what does that look like when we're actually maybe teasing apart those mid-analyses?

 

Jonathan Blau (02:42.116)

That's a great question. The history of the evidence. We have evidence approaching 20 years on probiotics. Many patients have been studied. JAMA Pediatrics, of course, published the largest meta-analysis to date at the end of September of over 25,000 patients who have received probiotics.

 

Now the problem with research in our field is that we often don't have a large enough N in one institution or with one intervention that's being studied to show statistical significance. So as you mentioned, the body of evidence really focuses on meta-analyses. There are many individual studies. But these studies, they have not all...

 

looked at intervention with the same probiotic. We have single strain, we have double strain, we have triple strain. We have pre-, they were given to pre-terms as a group, which is less than 37 weeks, of course. Some of them were just for ELBWs, some of them were just for VLBWs. But this whole pool of evidence in the meta-analysis form, and there have been several meta-analyses,

 

including that largest to date at the end of September of this year, they show a quite significant reduction in NEC from meta-analysis to meta-analysis. We're looking at 30 to 40 percent. If you, you know, consider all things being said, this is the one of the most studied interventions in neonatology and what we're seeing is something that we had not seen.

 

for a long time, you know, really since the advent of donor human milk programs across the country and the world in our units. And that is an intervention that is such a significant reduction with one of the scourges of our field, necrotizing enterocolitis.

 

Daphna Yasova Barbeau, MD (she/her) (04:48.36)

And before we kind of jump into the individual studies, which we will, I'm hoping you can talk a little bit about the, you know, the data behind, you know, the pathophysiology of even, you know, thinking about using probiotics to, to treat, but really prevent NEC.

 

Jonathan Blau (05:07.815)

Sure. So the pathophysiology of NEC, of course, is far from straightforward. It's far from simple. You know, this field going on 30 years plus, we really don't have a great understanding of NEC and we don't have a great understanding of how to prevent it, although we have made tremendous improvements. I mentioned donor human milk and things like that. But what it really all seems to be about...

 

You know, the hot topic the last year or two is the microbiome. Premature babies as a group, they are at risk for dysbiosis. And I would say most or all of them have dysbiosis. And this inappropriate bacterial colonization really is one of the major players in the pathophysiology of NEC. Now when the babies, the premature baby is born, they're really born with...

 

you know, far from a clean slate in terms of the microbiome. And that's how this relates to NEC. Most of the majority of preterm babies in the United States are born by the cesarean section. So they are not appropriately colonized with the commensal bacteria by passing through the vaginal tract. Many of their mothers are unwell. That's why they've given birth to premature babies and they have received antibiotics, which right away cross the placenta.

 

and begin killing off any good or bad bacteria in the fetus. The children are born, they are admitted to this hospital environment, which we know is not colonized with good healthy bacteria in the NICU setting. And then many babies, of course, for many years, have gotten broad spectrum antibiotics at birth, at admission, so you're really finishing off any.

 

good bacteria that was left. We used to give these babies formula before the advancement in donor human milk, and so there was really no path to introduce immunoglobulins. Donor milk is better than formula, of course, but it's not as good as MOM, mother's own milk. So this really is the perfect storm in an immune-compromised host.

 

Jonathan Blau (07:32.487)

who does not have proper innate immunity to be at risk for something like NEC, which immunologic dysfunction and poor bacterial colonization is a major pathophysiologic contributor.

 

Jonathan Blau (07:58.739)

address this significant dysbiosis that most of our patients have when they walk in the door or within 24 hours of being born. So the goal is to appropriately introduce commensal healthy bacteria and begin to repair some of this dysbiosis picture and the damage to the microbiome that's already happened.

 

And that's kind of the general thought for why probiotics work for NEC prevention.

 

Ben Courchia MD (08:36.138)

And for people following along, we'll link all the articles that we mentioned in this episode in the show notes. I believe the paper you referenced is the one in JAMAPEETS called probiotic, prebiotics, lactoferrin, and combination products for the prevention of more mortality and morbidity in preterm infants, a systematic review and network analysis. That's like a three line title, but very, very explicit. I wanted to

 

Jonathan Blau (08:48.567)

Yes, that's correct.

 

Ben Courchia MD (09:04.582)

I wanted to maybe get your sense in terms of the data as to, you mentioned that there's a lot of inconsistencies in the study of probiotics. And we see this over time where, number one, the patients that are studied are not always the same. As you mentioned, sometimes there are some studies where the babies are quite big. And considering today, looking back at some of these studies, right, where maybe...

 

maybe some of the initial studies for our field are coming from like the 1990s, where really at that time, the babies that were considered possibly the most vulnerable may not be the most vulnerable today, considering the edges of viability, the survival of babies in around 22 weeks, 23 weeks. So can you tell us a little bit about, even though there's been so much variability in terms of the patients studied, in terms of the probiotics studied,

 

Can you tell us a little bit as of today, what are the concrete benefits of probiotics in reducing the incidence of necrotizing enterocolitis in what we would consider a vulnerable population that has been studied? So where do we stand today? Because I think many people have gathered that qualitatively the benefit is there, but how much benefit, how much can probiotics slash NEC?

 

on these larger trials.

 

Jonathan Blau (10:32.66)

I think that's an excellent question, Ben, and it's really something that's on.

 

that's on everybody's minds these days, especially when we're looking at meta-analyses, what have they shown and what haven't they shown. And your point is well taken. You know, 20 years ago plus, the premature infant that, you know, if there was an incubator podcast back then discussing was it was a very different type of patient. But we are all familiar with the tremendous.

 

medical advances that we have all been a part of, everyone in this field, and we are now resuscitating 22 and 23 weekers. And of course, there's an inverse relationship between gestational age and the incidence of NEC. So NEC is not going anywhere. We are seeing, we will continue to see it despite our advances in NEC prevention because we are saving smaller.

 

and sicker babies where the risk is that much higher. I think another important point to make, I think that the neonatology community with a relatively small patient sample size, we're not internists studying myocardial infarction, we don't have those numbers, we never will. I think we've done a very good job with increasing the quality of research, the quality of trials, and as we saw to that meta-analysis,

 

the recent one you just mentioned, and JAMA pediatrics in terms of the size. We went from about 10,000 premature babies in the more recent meta-analysis to over 25,000 in this one. But as the quality of our research has improved, we are seeing more research of probiotics with the smaller, sicker babies. And to...

 

Jonathan Blau (12:28.667)

to what you were alluding to, I think that's where the money is at. When the smaller sicker babies get NEC, often it's more severe as well, probably because of an even more exaggerated immune dysregulation. But we have studies now that are looking, plenty of studies that are only looking at BLBWs and probiotics. And if you look at...

 

A paper from earlier this year from Dr. Chirivalu at Baylor's, she looked at VLBWs receiving a triple-strain probiotics compared to historical controls who were not. And her paper, while it's on VLBWs, there is a very large ELBW kind of subsection within her patient population. And those are things we were not seeing in the past. So my thoughts are the...

 

quality of our research is improving in terms of addressing this important question that you bring up. Another thing to remember is when you look at the general preterm population, so those older studies that you referenced, by far the largest patient population within our preterms are the late preterms. By far that's the largest.

 

you know, center to center, level four, level three, level two, but overall the late preterms are the largest. The second largest are the DLBWs and of course the smallest patient population of the L-GANS are the ELBWs. So it's harder to do a large study of the smallest and sickest patients because there simply are not as many of them as the older preemies, but we are addressing that and I think we're doing a good job going forward.

 

Ben Courchia MD (14:21.166)

Yeah, I think the paper that you're referencing is something I think that we reviewed on the podcast called effects of prophylactic probiotic supplementation on infants born very preterm or very low birth weight. And while the study is quite an impressive one where they had about maybe a bit over but 250 babies when they specifically, as you mentioned, looked at their... These looked at very preterm or very low birth weight infants.

 

Jonathan Blau (14:32.921)

Yes.

 

Ben Courchia MD (14:49.398)

But what was interesting is that in this study, they did have a specific outcome report for extremely low birth weight babies, which was very interesting. And then obviously the numbers were much lower. I think in that case, we were looking at more like 40 patients in each category, but the rates of NECs were dramatically reduced from about 14% in the babies that were not receiving probiotics to zero.

 

in the category that was receiving probiotics, which was an even more pronounced result from the broader category, which looked at a difference of like 6 to maybe 2%. So still a pretty impressive reduction. All the while, these numbers, I think because of the sample size, never really reach statistical significance. I think these are results that give us a bit of pause for reflection.

 

on what the effects of probiotics have been. I get, yeah.

 

Jonathan Blau (15:50.015)

Listen, the proper way to do a study, if we could design it, we are going to have tens of thousands of ELBWs. If this is the question we're looking at, the patients most at risk for severe NEC disease. Tens of thousands, multi-center, or whatever the number is that the statisticians concluding we need.

 

So tens of thousands of patients and they're all going to be studying the same probiotic preparation and we would have to decide which one that is. And then again, you know, I tell our trainees all the time, the best study of an intervention in the unit does not simply include, you know, outcomes from admission to discharge. You need neonatal follow-up as well. And, you know, looking at ELBWs to have a large volume.

 

patients to study that, including follow-up, that's really quite challenging. I hope we get there one day, but that's a big task for us as a field to accomplish.

 

Jonathan Blau (17:01.856)

Ben, I cannot, well, yes. I hear you now.

 

Daphna Yasova Barbeau, MD (she/her) (17:01.947)

when you're muted.

 

Ben Courchia MD (17:02.306)

Sorry, sorry, I was muted. I was muted, my bad. Yeah, so sorry, I was muted. But since you're talking about study design, you've alluded to neurodevelopmental follow-up. I'm curious to get your take on multi-center trial for probiotics because we see that...

 

especially we'll talk about the FDA involvement in a little bit. However, we're seeing that there's a lot of different stages at which people are, depending on which country you're in. So whether you're in Canada, whether in Europe. And so I'm wondering if in your opinion, this will have to be something that for us, at least in the U.S., will have to be tackled internally or that there's still a possibility for us to do a more international trial. Because as you alluded to.

 

studying extremely low birth weight babies is extremely difficult if you're not gathering data from other centers. So do you think that's still possible in today's day and age to have a multinational multi-center trial on probiotics and keep that consistency of keeping a homogeneous patient population and maybe using a more consistent product?

 

Jonathan Blau (18:18.503)

I think that we have to be open-minded and proactively go towards whatever pathway is going to lead us to the best research that we can get in this field. The next society last month.

 

Ben Courchia MD (18:22.016)

Mm-hmm.

 

Jonathan Blau (18:36.735)

published a paper, not a paper, a basic position paper on kind of where the next society stands right now and their goal is admirable, no more NEC, period. And I think that is a very important part of what has been going on recently, the discussion about what's been going on most recently, no more NEC, period. But they also noted and they referenced a couple of meta-analyses.

 

Daphna Yasova Barbeau, MD (she/her) (18:55.881)

about what's going on.

 

Daphna Yasova Barbeau, MD (she/her) (19:01.239)

And they referenced a couple of meta-analyses that in the past 20 years, the United States has lost about 500 patients a day. A year, excuse me, 500 patients a year. This is not acceptable for us as a field and we need to do better. I think we should collaborate with whoever.

 

Jonathan Blau (19:03.759)

that in the past 20 years, the United States has lost about 500 patients a day, a year, excuse me, 500 patients a year to NIC. This is not acceptable for us as a field and we need to do better. And I think we should collaborate with whoever can work with us, national, international, that certainly doesn't matter. I think working with the international folks would actually be very helpful.

 

because they do not have the same regulatory constraints that clearly we have found ourselves with. They have more experience in probiotics, they've used, more of their centers have used it and it's been for some time. So I would be open to whatever pathway, you know, we need to follow and I suspect that working with our international colleagues will be extraordinarily helpful.

 

Daphna Yasova Barbeau, MD (she/her) (19:58.519)

And to follow up on that, you know, you've spoken about some of the confounding factors that have...

 

Jonathan Blau (20:05.508)

Ben, you're muted again.

 

Ben Courchia MD (20:09.282)

Hold on one second, Daphna?

 

Daphna Yasova Barbeau, MD (she/her) (20:11.447)

Uh huh. Can you hear me? You can't hear me. Oh.

 

Ben Courchia MD (20:14.334)

you need to log back in and turn. Yeah, we can hear you, but there's a significant delay and we have a big echo. So you need to come back in and turn on echo cancellation. Like click that as if you're not using headphones. But yeah, all right. I'm going to keep going here. I'm so sorry about this. I try to mute myself so that there's no extra noises. And then there are some days like this. I'm post call today, so I'm forgetting to turn on my echo cancellation. Apologies.

 

Daphna Yasova Barbeau, MD (she/her) (20:24.148)

Let me see. Yeah, yeah, I see.

 

Jonathan Blau (20:31.192)

No problem.

 

Jonathan Blau (20:38.858)

Oh no.

 

Ben Courchia MD (20:41.546)

My question for you, Jonathan, was going to be, do you have a sense as to where other groups stand when it comes to their use of probiotics? For example, what is the practice, for example, in Europe, and how do they tackle some of the issues that we've already mentioned when it comes to different products being available, and so on and so forth? Maybe which population is considered the most at risk, considering how they're balancing which is the population most at risk versus...

 

population that also has enough evidence to support its use. Can you tell us a little bit about that?

 

Jonathan Blau (21:16.797)

Sure. So we have some good data from the Vermont Oxford Network folks back in 2021 where they looked at patients in the network, of course, around the world, units around the world in their network from 2018 to 2020.

 

And because Vermont Oxford, of course, if you look at the form, it didn't always, but it has been asking about did this patient receive probiotics, yes or no? You know, that's a relatively newer question for the Vaughan database. But they published the use of probiotics by Vermont Oxford Member Center by geographic area. And the Europeans were about 49%.

 

Asia, I believe, was in the 30s. North America, not surprising, the lowest at 13.7%. And we have to remember Canada, Canada has a far higher use of probiotic rate than the United States, so we were probably much lower. Regulatory environments are extremely different in...

 

Ben Courchia MD (22:24.814)

Mm-hmm.

 

Jonathan Blau (22:29.375)

in Europe, in Canada, in Japan, in Israel, in many other countries around the world where there is much higher probiotic use, probiotics are regulated completely by those countries' counterparts, the FDA. So in Europe, the European individual countries, you know, counterparts of the FDA, they regulate probiotics.

 

The triple strain probiotic that our center used for almost three years was actually only manufactured in Denmark. It's a bit ironic because the Danish version of the FDA regulated that product. It was exported to the United States and used, but it did not undergo further FDA scrutiny because no probiotics do. That's kind of the controversy in which we find ourselves.

 

But in Europe, I think, and many of this, I think, is cultural about European societies and attitude in general towards probiotics, as well as the regulatory environment, but they have been the highest users of probiotics for years. In Canada, the Canadian Pediatric Society, they recommend universal use of probiotics for all babies above birth weight, above one kilo.

 

And it's probably because it's considered by them that there are insufficient numbers of ELBWs that have received probiotics yet, back to that same research conundrum. But I think in Europe, it's done properly, or as ideally as possible in terms of regulation.

 

and cultural acceptance and the fact that it's really used by what I assume now is more than 50% of folks.

 

Ben Courchia MD (24:28.178)

Yeah, it's interesting how the Canadian recommendations echo a little bit the AAP recommendations that we're going to speak about with another guest in an upcoming episode where they do highlight this issue of not having too much clear-cut data for babies less than a thousand grams. So I think that's interesting as well. I know Daphna had one more question on study design, so I wanted to let her ask that question before I move on to another topic.

 

Daphna Yasova Barbeau, MD (she/her) (24:58.687)

Yeah, since we've kind of alluded to it, I wonder what would be the optimal study design if you could have everything you wanted? I mean, obviously we'd study little babies and it'd be multi-center, but what would the strain look like? What would the other feeding look like? What would skin-to-skin look like? What other things would you control for if you could have the optimal design for probiotics?

 

Jonathan Blau (25:07.662)

I'm going to take a few minutes to get this done.

 

Jonathan Blau (25:28.514)

Wow, so I'm getting a blank check. That sounds wonderful.

 

Ben Courchia MD (25:30.978)

Blank check, blank check, full multimillion dollar funding from the Daphna Barbeau Foundation.

 

Jonathan Blau (25:39.215)

Very nice. Well, of course, I would take as much advice as possible, but for this theoretical question it was up to me. This would certainly be multi-center. We need to get as many patients as possible. I personally would limit this study. The inclusion criteria would be BLBWs, and we would really have to make an effort to include as many ELBWs within that population as well.

 

you know, similar to the Chirivalo paper that we discussed earlier. In terms of which strain, that's a very important question. It's debated, it continues to be debated, it probably will continue in the future. I'll tell you what we did in our center, and this was about at least a year of thoughts and discussions over which product to use, because there are many products on the market. We chose the triple strain.

 

b infantis, be lactis, and Thermophilus. And we chose that strain because ESPGAN, the European Society for Pediatric Hepatology and Nutrition, they're really a great organization. Even though they're a PEDS GI organization, they continue to publish a lot of position statements and evidence-based-backed opinion pieces on preterm nutrition. They revise their...

 

preterm nutrition guidelines earlier this year, for example. But ESP began for the first time back in 2020 or 2021, I'm forgetting, I think it was 2020. They looked at 11 different probiotic preparations and they looked at the evidence behind all of them and they recommended really just one for general.

 

use for preterms and it was the B. infantis, B. lactis, and Thermophilus strain, probably because those are very prevalent in breast milk. And that is the reason why we chose the triple strain product that has those three probiotics. So if you look ahead to the AAP statement that came about the following year in 2021, they urged general caution. They said,

 

Jonathan Blau (27:58.419)

universal provision of probiotics to everyone, but they also commented that single strain should not be used and they referenced the ESPGAN guidelines from the year before that commented how that triple strain was a reasonable evidence-based recommendation. So that is what the strain that I would choose, again, based on that ESPGAN recommendation. We have not seen any other professional societies to date, to my knowledge.

 

that have recommended probiotic strain A versus B since that ESPGAN paper. And the ESPGAN, they're really, they're a great organization, and I personally trust them and put a lot of stock into what they say. So the triple strain is recommended by ESPGAN, multicenter as the best that we can do in the United States, given the limitations here that we have versus Europe, Canada, et cetera, in conducting, you know,

 

multi-center, you know, we're never going to get every center in the country like, you know, they do in Australia and New Zealand, for example. But that's kind of how we would handle it. And we should look at growth data, nutrition data, you know, growth failure at discharge data, NEC, laser, and sepsis, you know, all the things that have kind of been looked at in different studies, but look at all of them. And then again, you know, if I am getting that blank check.

 

We look at neurodevelopmental follow-up as well.

 

Ben Courchia MD (29:31.754)

Jonathan, as we're wrapping up our conversation about quote unquote the data, I am just curious about whether you can share with us a little bit about what are some of the other benefits of probiotics. I think there's been a lot of discussions and especially as we're going to get into this whole FDA memorandum, but what does it do for death, for length of stay, for sepsis?

 

As we've gathered that the effect of probiotics on NEC is quite pronounced and there's quite a lot of evidence to support it, how are we looking when it comes to these other morbidities specifically?

 

Jonathan Blau (30:15.127)

Sure. So you're absolutely right, Ben. The benefits are not limited to just NEC. I think we all focus on NEC because NEC is really a thorn in all of our sides as it should be, you know, and again, I'm repeating the NEC society's very admirable call to no more cases of NEC ever, period. That's something I think we would all like to see. But it's not just NEC. It's late onset sepsis, which has been shown in multiple trials as well.

 

Ben Courchia MD (30:26.958)

Mm-hmm.

 

Jonathan Blau (30:44.531)

on the combinations of NEC and mortality or morbidity and mortality that goes down as well. Some of the meta-analyses have shown reductions in mortality, improvements in length of stay, and there's also data that shows better growth and nutrition outcomes really in the past couple of years. That's a relatively new kind of conclusion that we are seeing among research in the field. So there are many benefits that we're seeing.

 

and it's not at all just SNEC.

 

Ben Courchia MD (31:18.794)

Right. When we're talking about sepsis, I think there's something to be said, right? Because one of the big concerns about probiotics is that, hey, you're introducing a live... Like, we don't like live stuff. We don't like live vaccines in the NICU. But live bacteria is something, obviously, that gives us pause for concern because culture proven sepsis is one of these things that we want to prevent at all cost.

 

Jonathan Blau (31:35.815)

Hehehe

 

Ben Courchia MD (31:49.146)

The data is showing that there is a reduction in the rate of culture proven sepsis. I think the paper that we were recently mentioning in JAMAPEDES gives a good outline of that, looking at different types of probiotics, multistrains versus single strains. Do we think that there is enough evidence to definitely say that the risk of...

 

culture proven sepsis is not something that is it, because sometimes we have data that shows one thing, but it could be still equivocal. What do you think about that?

 

Jonathan Blau (32:26.291)

So, I think we're talking about culture positive sepsis and what we'll just, we'll just going forward in this talk, I'll just say sepsis. Sepsis means positive culture, not culture negative sepsis. I think there's two types that we need to talk about here. The historical late onset sepsis, GVS, E. coli, Klebsiella, Enterococcus, you know.

 

Ben Courchia MD (32:37.422)

Mm-hmm.

 

Jonathan Blau (32:51.307)

MRSA, all these things that we see among our patients in the NICU, unfortunately. And then there's the entity of probiotic-associated sepsis. And probiotic-associated sepsis, there are some other terms as well to describe the same phenomenon. It's when we are giving the live bacteria, as you mentioned, the probiotics to our patients for prophylaxis or whatever reason we're giving it. Let's say for NEC prevention.

 

purposes of this discussion and the child is doing fine. And then a couple of weeks later, I'm kind of making up a case as I go along here, the child is on cannula or a small amount of respiratory therapy and they start to have symptoms consistent with sepsis. We take a culture, we start broad spectrum antibiotics, the things we always should be doing in that situation.

 

Jonathan Blau (33:49.291)

bacteria that is the probiotic that we have been giving to this patient. So that's probiotic associated sepsis. That is something we should have no tolerance for. There should be zero cases, you know, do no harm and all of that. But I think one of the things we need to remember here, and ESPGHAN certainly touched upon it, the AP alluded to it as well,

 

And that's something we need to, I think especially now the past couple of months, we really need to focus on. Not all probiotics are the same. Not all probiotics have the same benefits. Not all probiotics have the same risks. And then you reference that JAMA-PEDS study right now, which is a perfect time to bring that up again, because they showed that the best benefits were in the multiple strain.

 

on probiotics, both in mortality and morbidity. We have had advice since ESPIGAN in 2019 and doubled down by, excuse me, 2020 and then reaffirmed with AAP, we should not be using single-strain probiotics. There are many probiotics, single-strain probiotics on the market, and I think we're all familiar of that extremely tragic case of an ELBW.

 

that we learned about at the end of September of this year who had a mortality with the probiotic-associated sepsis. But we should not be using single strain. The single strain versus the multiple strain, the triple strain that ESPGHAN recommended that's very prevalent in breast milk, that decision, one or the other, that's going to have a tremendous impact on immunologic response. And again, the...

 

appropriate healthy colonization of the microbiome of the GI tract that we're trying to accomplish. So I think we really need to refocus and not paint probiotics with the same, all probiotics with the same brush because they are quite different and it really does matter which probiotic one chooses.

 

Ben Courchia MD (36:01.146)

Jonathan, last question for today's episode. I wanted to ask you since we're a little bit of a standstill when it comes to probiotics in the US with the FDA, and we'll talk about that in tomorrow's episode, but do you see maybe probiotics entering the NICU in a different manner? For example, babies who are much older but who are on prolonged courses of antibiotics. I'm thinking your 21-day meningitis baby who gets really strong antibiotics for a prolonged period of time.

 

And we know that in adults, probiotics in prolonged antibiotic courses is routine. Do you think that's potentially something that might come back and maybe provide a sort of back door for probiotics to slowly be reintroduced in the NICU in the U.S.?

 

Jonathan Blau (36:45.021)

Listen, I think the data for probiotics is there.

 

I think we should use probiotics really to the extent that we are able to in this current environment of the past two months. You know, a full term baby who has meningitis for three weeks, you know, that kid is going to have a really damaged microbiome, but if it's a full term baby...

 

Risk of NEC is not zero, it's a sick full term baby, but it's not the same issue as talking about a 23-weeker in terms of risk of NEC. Other indications that folks have used for probiotics are neonatal abstinence syndrome, you know, now that's really...

 

kind of taken off. We don't have evidence for that. We need to have evidence for that. But there is a lot of anecdotal experience with that. And a lot of neonatologists, especially in areas in the United States, you know, particularly devastated by the opioid epidemic and seeing, you know, tremendous amounts of nows, that there are some units, even level 3s, that, you know, I've spoken to folks, more than half of their units are nows babies. They're reporting anecdotally.

 

significant benefits with probiotics. So I think we should continue to use it, you know, whenever we can to help our patients. That's what we should be doing. But I don't want us to lose track, lose sight of what I would like to see happen is for us to have a return to probiotic use for NEC prevention, albeit in a very different

 

Jonathan Blau (38:36.623)

kind of pathway to get there that we've seen in the past.

 

Ben Courchia MD (38:40.106)

Fair enough, fair enough. Dr. Jonathan Blau, thank you so much for making the time to be on with us today. We will see you again tomorrow to continue this discussion. It was fun, thank you.

 

Jonathan Blau (38:52.271)

Thank you Ben and Doc, that was a pleasure.

 

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