The FDA are at it again, they seem to be on a mission to go after suppliers of probiotics for preterm babies, and have now attacked Abbott. They appear to have demanded that they stop marketing their probiotic product, as it is not an approved medication, and could be considered an adulterated food product that is not GRAS (Generally Regarded As Safe).
I don’t know if it will be possible to get the FDA to back off. They need to realize that all breast-fed babies are already receiving probiotics. In a completely unregulated way. Every baby that gets unpasteurized breast milk is getting some sort of bifidobacteria, and probably lactobacilli, as well.
If breast-milk isn’t GRAS, I don’t know what is!
Bifidobacteria are usually present in fresh breast milk, although sometimes in very small amounts, and mixed with a huge variety of other organisms, the microbiome of milk varies between individuals and varies around the world, and it seems to be changing over time. Even among babies whose mothers’ milk contains few bifidobacteria, the infants become overwhelmingly colonized with bifidobacteria within a few days, for as long as they are breast fed. Babies born by cesarean delivery, and/or who receive antibiotics in the neonatal period, develop a very different microbiome, which I don’t think is too far of a stretch to call “abnormal”; there is an increased frequency and relative abundance of various pathogens, including E. Coli, Klebsiella, and others.
Once a baby is admitted to the NICU, if we consider the preterm at risk of NEC, intestinal bacterial colonization proceeds with the organisms present in the environment, on the equipment, and in their feeds.
I think of administering probiotics, Florababy(TM) in the case of our NICU, as an attempt to push the microbiome towards normality. I know that despite routine administration of probiotics, the microbiome of the babies in my NICU will remain abnormal, and we will still have cases of late-onset sepsis and NEC. Even, occasionally, of sepsis caused by the organisms that we give purposefully. But we cannot avoid giving the babies enteral organisms! They will become colonized whatever we do, and without probiotics the balance will be more towards pathogens.
The best way to nudge the intestinal microbiome towards being normal is to :
- Ensure that all the babies receive unpasteurized mother’s own milk as soon as possible after delivery. There may be additional benefits of using colostrum for the first feeds.
- Avoid antibiotics, or limit them to the fewest babies for the shortest time possible
- Continue to feed with mother’s own milk, or if unavailable/insufficient, use donor human milk
- Administer a high-quality probiotic preparation. My best guess is that it should contain B longum ssp infantis, and at least one other organism, perhaps Lactobacillus rhamnosus
Adding human milk oligosaccharides, HMOs, especially DSLNT (disiallylo-N-tetraose) improves colonization with Bifidobacteria, and further normalises the microbiome. It is fascinating to reflect on the fact that human milk contains oligosaccharides that humans cannot metabolise! They make up a major proportion of the solids in breast milk. Bifidobacteria have a unique pathway, the Fructose-6-Phosphate Phosphoketolase system, that allows them to metabolize those HMOs, and as a result to downregulate inflammation. They create communities in our guts where multiple species co-operate, which has been referred to as “altruistic” behaviour.
In the future, I think that additional specific HMOs will probably be added to my list of microbiome interventions; if the FDA permit it.
One thing we cannot do, and should not try, is to keep the preterm infant’s GI tract sterile. Trying to ensure the most normal possible microbiome is an essential part of care of the extreme preterm. The FDA’s interventions will only ensure that intestinal colonization is more random, with more pathogens, and more cases of NEC will follow. The FDA seem really to want to kill preterm babies. The lack of insight into the impact of this intervention is startling.
As far as I can see, there is no current pathway for the approval of probiotics for administration to preterm infants. It should be a major priority of the FDA to create and facilitate such a pathway, this is an urgent need for preterm babies. And to back off from those who are currently supplying high-quality products in the interim.
Here are some of the references I used for this post.
Nolan LS, et al. The Role of Human Milk Oligosaccharides and Probiotics on the Neonatal Microbiome and Risk of Necrotizing Enterocolitis: A Narrative Review. Nutrients. 2020;12(10).
Egan M, Van Sinderen D. Carbohydrate Metabolism in Bifidobacteria. The Bifidobacteria and Related Organisms. 2018. p. 145-64.
Moossavi S, et al. Composition and Variation of the Human Milk Microbiota Are Influenced by Maternal and Early-Life Factors. Cell Host Microbe. 2019;25(2):324-35 e4.
Henrick BM, et al. Elevated Fecal pH Indicates a Profound Change in the Breastfed Infant Gut Microbiome Due to Reduction of Bifidobacterium over the Past Century. mSphere. 2018;3(2):10.1128/msphere.00041-18.
Kumar H, et al. Distinct Patterns in Human Milk Microbiota and Fatty Acid Profiles Across Specific Geographic Locations. Front Microbiol. 2016;7:1619.
Jeurink PV, et al. Human milk: a source of more life than we imagine. Beneficial microbes. 2013;4(1):17-30.
Biagi E, et al. The Bacterial Ecosystem of Mother’s Milk and Infant’s Mouth and Gut. Front Microbiol. 2017;8:1214.
Notarbartolo V, et al. Composition of Human Breast Milk Microbiota and Its Role in Children’s Health. Pediatr Gastroenterol Hepatol Nutr. 2022;25(3):194-210.
Chang CM, et al. Effects of Probiotics on Gut Microbiomes of Extremely Preterm Infants in the Neonatal Intensive Care Unit: A Prospective Cohort Study. Nutrients. 2022;14(15).
Baucells BJ, et al. Effectiveness of a probiotic combination on the neurodevelopment of the very premature infant. Sci Rep. 2023;13(1):10344.
van Best N, et al. Influence of probiotic supplementation on the developing microbiota in human preterm neonates. Gut Microbes. 2020;12(1):1-16.
Larke JA, et al. Preterm Infant Fecal Microbiota and Metabolite Profiles Are Modulated in a Probiotic Specific Manner. J Pediatr Gastroenterol Nutr. 2022;75(4):535-42.
Saturio S, et al. Role of Bifidobacteria on Infant Health. Microorganisms. 2021;9(12).
Patangia DV, et al. Impact of antibiotics on the human microbiome and consequences for host health. Microbiologyopen. 2022;11(1):e1260.
Murphy K, et al. The Composition of Human Milk and Infant Faecal Microbiota Over the First Three Months of Life: A Pilot Study. Sci Rep. 2017;7:40597.
Neonatal Research 
Very well put, Dr. Barrington.
In Israel we do not currently offer probiotics in NICUs, but we are working on changing this reality. Some of us believe in the huge potential of probiotics in preventing NEC and maintaining normal and desirable gut health.
Following recent events that caused the FDA to write an official letter warning healthcare providers from probiotics in the NICU, I wrote the following in a Linkedin post (can be found here: https://www.linkedin.com/posts/dotan-shaniv-73756211b_after-death-of-infant-fda-warns-hospitals-activity-7116301119244369920-v1Li?utm_source=share&utm_medium=member_desktop)
Probiotics in the NICU: Friend or Foe?
Several high-profile news channels, such as CNN (https://lnkd.in/d5AFHnnR) and CBS News (https://lnkd.in/d-aDqFMW), have reported last week about the unfortunate death of a preterm infant, suspected to be caused by a probiotic supplement, and the warning issued by the FDA as a “Dear Healthcare Provider” letter (https://lnkd.in/d2ppwzqU) in that regard. In its letter, the FDA cited the current position of the American Academy of Pediatrics: “…current evidence does not support the routine, universal administration of probiotics to preterm infants, particularly those with a birth weight of <1000 g".
While devastating, as any death in the NICU of any cause would be, it is important not to let this case overshadow the wealth of already available evidence, which shows clear benefit of probiotics in the development of neonatal microbiome and prevention of necrotizing enterocolitis. The CNN report itself referred to a systematic review and network meta-analysis on probiotics in preterm infants recently published in JAMA Pediatrics: https://lnkd.in/dDS3UXWm, which found a statistically significant decrease in all-cause mortality due to administration of multiple-strain probiotics (please note that in the abovementioned case, the infant received a single-strain probiotic supplement).
In other words, we must avoid the "fallacy of misleading vividness", i.e., the act of pushing aside a significant amount of evidence in favor of dramatic – yet anecdotal – evidence.
The position of the FDA and American Academy of Pediatrics towards probiotics is well-known, as it exhibits an unrelenting policy of demanding robust data of the highest quality before giving any product a seal of approval. However, one cannot disregard the long-standing experience of other countries, e.g., in Europe and Australia, where probiotics are routinely used and necrotizing enterocolitis rates are extremely low.
It is also important to remember that no medical treatment is 100% safe, including approved drugs and well-established procedures. Secondly, preterm infants are a highly fragile population, and may be prone to adverse effects (and even mortality) of any treatment, with the risk being inversely related to the infant's age and weight. Thirdly, the vast majority of medications used in preterm infants are used 'off-label' and in an unlicensed manner, due to paucity of clinical trials in this population.
I recommend listening to Dr.Sridhar Kalyanasundaram's opinion on the subject: https://lnkd.in/da63EAFM, as well as the special episode of The Incubator Podcast: https://lnkd.in/dTyTB4a6 featuring Drs. Ravi Patel and Rune Toms.
I totally agree with this post: the newborn gut is going to get colonized. The theory behind prophylactic probiotics is that “friendly” bugs are preferable to “unfriendly” bugs. What makes a bug friendly? Among other properties, under anerobic conditions they make lactate, which is a soluble liquid, not hydrogen (or other gas) which is insoluble and leads to NEC.
We recently found out that Renew Life is no longer going to make Florababy. What alternatives will you be using in your NICU?
We’re still investigating. A high-quality probiotic preparation is made in Europe, that includes a B Infantis, it’s supplied in Europe by Neobiomics and is called Proprems. It seems to be identical to the Abbott product, so that might not work in the USA, but I think probably a good option for Canada.