Last week there has been quite som buzz on the social media-site formerly known as Twitter, regarding a decision from the FDA to warn about the use of probiotics in preterm babies. This after a strain of Bifidobacterium Longum was found in a blood culture of a septic preterm infant weighing <1000 g, possibly contributing to the infants death. It was published on September 29th.

https://www.fda.gov/media/172606/download?attachment

My timeline was filled with people reacting with surprise and also being a bit put down. There has been more and more evidence piling up in favour of probiotic use, and it has been wide spread across many well known centers

Two days ago an excellent review was published: https://jamanetwork.com/journals/jamapediatrics/article-abstract/2810095

Showing Probiotics showing were associated with reductions in all-cause mortality, necrotizing enterocolitis, feeding intolerance and hospitalization.

Ravi Patel shared a fresh editorial from his team: https://jamanetwork.com/journals/jamapediatrics/article-abstract/2810100

And Kanekal Suresh Gautam shared these to articles in favour of use: 

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2804952

https://jamanetwork.com/journals/jamapediatrics/article-abstract/2780228

At the same time encouraging to study improvement of dysbiota by other means such as

• reduced antibiotics use
• increased use of mothers own milk
• Reduced use of PPI
• Decrease caesarians
• Prebiotics (as in pre not pro)
• Probiotics to mother
• skin-to-skin care

Jae Kim in Cincinnati summarized it as follows: 

As with every intervention we do there are always unfavourable outcomes, sometimes severe. Just inserting an UVC can induce a sepsis. What are your thoughts on this development, and how to move further? Have you implemented probiotics, and for which group of babies?

Such a nice overview of the situation!!!! Thanks @Gustaf Lernfelt for the work you put into this topic!!!

Thanks @Gustaf Lernfeltfor initiating this thread. 

 

I would say that What ever treatment we gave to babies , have side effects, and we already know that giving Live bacteria to baby, possibility of sepsis is there, but we take chance as once NEC is there, it is a very nasty disease, with lot of complications affecting future life of baby and family. 

I think it will be difficult now ( at-least in USA) after that FDA letter, that neonatologists will dare to start on Probiotics. We may see increase surge of NEC more in coming many months in USA, and it will be a good QI project one can start and see pre and post FDA letter increase in NEC cases in unit where probiotics was initially given and now it was held.

Time to promote more Human milk availability, less use of antibiotics, early CVL removal, consider the principle of less is more and Outside USA consider or continue using Probiotics if your baseline risk of NEC is high as we can’t ignore the fact that Probiotics Prevent NEC.

 

Could this also perhaps be about the regulation,  manufacturing, licensing issues around the use of probiotics? That they are not a “drug” as such, and therefore the quality/preparation of individual products may be different? 

 

“The FDA is also reminding healthcare providers that FDA has not approved any probiotic product for use as a drug or biological product in infants. The FDA is aware that some unapproved, unlicensed probiotics are nonetheless sold for use to treat or prevent a disease or condition in infants, including to reduce the
  risk of necrotizing enterocolitis (NEC) in preterm infants. Healthcare providers should be aware that these products have not undergone the FDA’s rigorous premarket review evaluation for safety and effectiveness, nor have they been evaluated for compliance with the agency’s rigorous manufacturing and testing standards for drugs and biological products, including testing for extraneous organisms”

For further insights in this discussion, an extra episode of the Incubator podcast was just released discussing current knowledge.

 

Here’s a fantastic summary by Keith Barrington, definitely worth reading: 

https://neonatalresearch.org/2023/10/06/probiotics-what-now/

🍿🍿🍿

As for a Swedish regional setting we use a multistrain probiota for premature children below 32+0 if they weigh 1000 g or more, or are born after 28+0. Starting at 2-4 days of age or when the infant can tolerate 3 ml/feeding.

Treatment continues until 34+0, and is cancelled in case of NEC, if 0 per os before surgery, or sepsis with positive blood culture for any of the probiota-bacteria. Blood cultures need to be marked with info about treatment with the probiotic bacteria. If suspected sepsis or other bacteria are cultured treatment stays.

So preemies born earlier than 28 won’t be treated unless they whey 1000 g. How this alines with data on NNT and benefits, I have no clue about. A large portion of the most at risk children are excluded from the treatment group. But I guess it’s kind of a Swedish lagom-approach.

The reason for the unusual strategy in Sweden, to give probiotics to infants at 28-31 weeks and not <28 weeks, is because the national nutrition group argued the evidence for infants <28 weeks was insufficient. The result of this discussion was to recommend in the very preterm population (28-31 weeks) and make a full-scale RCT in extremely preterm infants (<28 weeks), the PEPS trial, see link below. It is currently running and hope to present results in a few years time.

The plan is ambitious, to randomise 1600 infants <28 weeks, so it might take longer. 

https://clinicaltrials.gov/study/NCT05604846

My thoughts goes like this, that not much will change. If I may make an analogy to politics: I foresee few people shifting between the Probiotics Positive Party and the Probiotics Sceptics Party.

So, the positive ones will keep being positive (thanks to strong arguments from key stakeholders), while the sceptic ones will feel they get new fuel for their position.

Everyone has an opinion, and all of these are valid. For me a few random comments -  

1. A definitive trial powered on NEC requires n>3,000 and may never be performed; so in 10 years time we will still now know for certain. What will happen is that NICUs that use, will publish cohort studies, and slowly we will get an idea of which combinations appear most effective. 
2. The WHO are funding a trial in LMICs which might (or not) provide information for high income settings. But a negative result might simply reflect the context (biomes, risks and benefits are different in Africa v Asia v Europe)  - so we might still not know
3. In 2033, another 10 years of observational studies will further prove the safety of probiotics ( 1 death per 10,000s exposed is very low rate). Invasive sepsis is not related to QC/QA (contamination is)  - so you can't decrease the risk of invasive sepsis by manufacturing a "better" product. However, the MCT oil in the FDA case is interesting - did the MCFA provide a direct conduit for the Bifido bacteria to enter the blood stream?
4. There are major risks of commercial involvement  - investment of $millions to develop and test a product mean they will use very heavy handed legal powers to shut down smaller manufacturers. Beware! 
5. The way forward is via parent/public pressure and advocacy. Parents can look at a Cochrane plot and can easily understand the debate - it is not that complex! You don't need to start probiotics day 1-2 it is OK to wait whilst parents consider the options and have a slightly better understanding of NICU. Parents can request their baby is treated in the same way they can request/decline donor milk. In a litigious medico-legal environment (USA) parents could be offered the information and sign an agreement to say they want their baby treated.
6. I have little sympathy for the FDA - their statement will increase deaths. However, I have some sympathy with the AAP statement. I don't agree with it, but it is very difficult for an organisation like the AAP in a US legal environment to be so definitive. As clinicians, we need to stick together. We all want the same thing. None of us is making money out of the debate! So please keep opinions "tempered" - it is through disagreement and respectful discussion that we will improve care.

have a nice day! Nick 

I find the statement hippo critical,  considering all the litigation on the use of formulae milk and its association with NEC . 

https://www.millerandzois.com/nec-baby-formula-lawsuit.html  https://www.thegomezfirm.com/baby-formula-lawsuit/  https://www.classaction.org/nec-premature-infant-formula-lawsuit https://www.shouselaw.com/torts/baby-formula-lawsuit/

Yet I have not seen a FDA response to this topic 

 

Ricky Dippenaar

 

 

On 10/7/2023 at 6:07 AM, Gustaf Lernfelt said:

As for a Swedish regional setting we use a multistrain probiota for premature children below 32+0 if they weigh 1000 g or more, or are born after 28+0. Starting at 2-4 days of age or when the infant can tolerate 3 ml/feeding.

Treatment continues until 34+0, and is cancelled in case of NEC, if 0 per os before surgery, or sepsis with positive blood culture for any of the probiota-bacteria. Blood cultures need to be marked with info about treatment with the probiotic bacteria. If suspected sepsis or other bacteria are cultured treatment stays.

So preemies born earlier than 28 won’t be treated unless they whey 1000 g. How this alines with data on NNT and benefits, I have no clue about. A large portion of the most at risk children are excluded from the treatment group. But I guess it’s kind of a Swedish lagom-approach.

We have a similar approach in Calgary, Canada, for the same reason. I guess it is not only the Swedish approach.

We saw this in two cases at the beginning years ago. Then we stopped giving probiotics for a time and changed the product and haven't seen any problems since, even with the small weeks. We are convinced of it

"Can I ask which type of probiotics you are using, Katja? Which product did you use before, and which one are you using now?" Thx for sharing 

@M C Fadous Khalife I think the product/brand as such may be of less importance, one needs to consider the risk of bacteremia/septicemia with probiotic strain, regardless of product used.

However, "baseline risk" (i.e. probability) of such bacteremia/septicemia is most likely very very low, given what is reported.
This systematic review came out in 2022: https://link.springer.com/article/10.1007/s00431-022-04452-5

So, as with everything we do in the NICU, one needs to balance benefit vs risk

@Stefan Johansson Thx for your answer. I attended'' Journées Parisiennes de Pédiatrie '' in Paris, 5-6 October where all conferences were for probiotics use, and then saw what was posted on October 4. We needed to clarify it. Best, 

ESPGHAN and EFCNI recently published a joint statement on the issue available here:

https://onlinelibrary.wiley.com/doi/full/10.1002/jpn3.12204