FDA Warns That Probiotics Given to Preterm Infants Can Cause Fatal Infections (2023)

Table of Contents

1. What the FDA Did
2. The Infant Death Behind the Warning
3. Why Preterm Infants Are Treated Differently
4. Why the Products Counted as Drugs and Biologics
5. The Food-Law Findings: GRAS, Food Additives and New Dietary Ingredients
6. The Two Warning Letters
7. What the FDA Said About the Evidence
8. What the Warning Does Not Do
9. Dates and Legal Status as of 18 October 2026
10. How the Warning Fits Later FDA Steps
11. Primary Documents
12. Key Research Papers
13. Connections
14. Featured Videos

1. What the FDA Did

The action had three parts, all from the FDA itself rather than a new regulation:

• A letter to healthcare providers (29 September 2023). Titled “Warning Regarding Use of Probiotics in Preterm Infants” with the subject line “Risk of Invasive Disease in Preterm Infants Given Probiotics Formulated to Contain Live Bacteria or Yeast,” it was signed by Peter Marks, M.D., Ph.D., Director of the FDA’s Center for Biologics Evaluation and Research (CBER), and Donald A. Prater, D.V.M., Acting Director of the Center for Food Safety and Applied Nutrition (CFSAN). It describes itself as “important safety information to healthcare providers on the use of products containing live bacteria or yeast (commonly called probiotics) in preterm infants in hospital settings.”
• Two warning letters (28 September and 24 October 2023). Both were issued by CBER and signed by the compliance directors of CBER and CFSAN, to two companies selling probiotic products for use in preterm infants in hospitals (section 6). In the letters’ own words, each “notifies you of our findings and provides you an opportunity to address the above deficiencies.”
• A news release (26 October 2023). “FDA Raises Concerns About Probiotic Products Sold for Use in Hospitalized Preterm Infants,” with the subheading “Warning Letters Issued to Two Companies for Illegally Selling Probiotic Products to Treat Diseases in Preterm Infants.”

The release states the agency’s concern: these products “can be dangerous for preterm infants and are being illegally sold to treat or prevent diseases in preterm infants in hospital settings, such as to reduce the risk of necrotizing enterocolitis.” Necrotizing enterocolitis (NEC) is an intestinal disease of preterm infants; the site describes it on its Necrotizing Enterocolitis page.

The 2023 steps were a safety communication and enforcement letters; none of them was a Federal Register rule.

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2. The Infant Death Behind the Warning

The letter to providers sets out the case in four points:

• A preterm infant with a birthweight under 1,000 grams (about 2.2 pounds) was given a probiotic as part of in-hospital care.
• The probiotic was formulated to contain the live bacterium Bifidobacterium longum subsp. infantis.
• The infant “developed sepsis caused by the bacterium Bifidobacterium longum and subsequently died.” Sepsis is a life-threatening response to infection; the site’s Neonatal Sepsis page covers it in newborns.
• “Genomic sequencing data demonstrate the bacterium that caused sepsis in this infant was a genetic match to the bacteria contained in this probiotic.” The FDA stated that it was investigating the death.

The news release places the death in a wider pattern. Certain probiotic products used in hospitals to prevent NEC “have contributed to invasive disease, including one infant death in 2023, and have been associated with more than two dozen other reported adverse events in the United States since 2018.” The agency added that it was “investigating reports that these products may have contributed to additional adverse events, including death,” and was working to obtain evidence and medical records where possible.

The provider letter also notes that the microorganisms in probiotics “have been reported in the medical literature as causing bacteremia or fungemia, sometimes with a severe clinical course, in very preterm or very low birthweight (VLBW) infants” — that is, bacteria or yeast from the product found in the blood. It cites four published case reports for this, listed under Key Research Papers.

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3. Why Preterm Infants Are Treated Differently

The release explains that probiotic products “contain live organisms such as bacteria or yeast and are commonly marketed as foods, including as dietary supplements.” The concern in 2023 was their use in one group: hospitalized preterm infants.

Both warning letters give the FDA’s reasoning in the same words. Preterm infants are described as “a highly susceptible, heterogenous subpopulation of varying ages (<37 weeks of gestation) and weight, who are physiologically, developmentally, and metabolically immature compared to healthy term infants,” with a high risk of illness and death and a need for specialized care, so that the agency has “greater safety concerns for this population than we have for a healthy term infant population.”

The letters continue: “Because their gastrointestinal system is not fully matured, preterm infants have more permeable intestinal linings, often referred to as ‘leaky guts,’ and motility problems, which can lead to opportunistic infections and sepsis when ingesting living microorganisms.”

Many such infants are cared for in a neonatal intensive care unit (NICU). One letter observes that “Preterm infants are often hospitalized in a NICU,” and both treat marketing for hospital or NICU use as evidence that a product was intended for preterm infants.

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4. Why the Products Counted as Drugs and Biologics

Under U.S. law, what a product legally is depends partly on what it is sold to do. The warning letters quote the companies’ marketing claims that probiotics reduce the incidence of NEC, and conclude: “Because these statements indicate that your product is intended for use in the mitigation, treatment, or prevention of disease, your product is a drug” under the Federal Food, Drug, and Cosmetic Act (FD&C Act). Each product was also found to be “a biological product” under the Public Health Service Act, “because it is applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

Two kinds of FDA application explain what was missing:

• Biologics License Application (BLA). To be sold lawfully as a drug that is also a biological product, a product needs a licence. The letters state that such licences “are issued only after a demonstration that the product is safe, pure, and potent.”
• Investigational New Drug application (IND). Before a licence, a product may be given to people for clinical use only under an IND. The release says that, in the absence of an approved product, healthcare providers who give live bacteria or yeast “to treat, mitigate, cure or prevent a disease or condition are required to submit an Investigational New Drug application to the agency to ensure the investigational use of an unapproved product is conducted with the appropriate safeguards.”

Neither product had an approved BLA or an IND in effect, according to the letters. The release adds the general point: “the FDA has not approved any probiotic product for use as a drug or biological product in infants of any age.” Unapproved products of this kind, it says, “have not undergone the agency’s thorough premarket evaluation for safety and effectiveness” and have not been checked against the manufacturing and testing standards for drugs and biologics, “including testing for other organisms.”

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5. The Food-Law Findings: GRAS, Food Additives and New Dietary Ingredients

Separately from the drug findings, the letters found that the products also broke food law when intended for preterm infants. Three terms explain how:

• Food additive and GRAS. The letters state that any substance added to food needs FDA premarket approval as a food additive “unless the use is generally recognized as safe (GRAS) by qualified experts” or meets another listed exception. “GRAS status requires publicly available evidence that the intended use is safe and a consensus among qualified experts that the intended use is safe (21 CFR 170.30).” The FDA wrote that “The current published literature does not show consensus among qualified experts that the use of living microorganisms in preterm infants is safe,” and concluded that the bifidobacteria in both products were not GRAS for use in food for preterm infants, making them unsafe food additives for that use and the products adulterated.
• Dietary ingredient. One product was labelled as a dietary supplement. The letter lists the legal categories of dietary ingredient (a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance to supplement the diet, or a concentrate, metabolite, constituent, extract or combination of these) and states that its bifidobacterium “does not fall within any of these categories,” so it could not rely on the dietary-ingredient exemption.
• New dietary ingredient. The same product’s Streptococcus thermophilus strain was found to be a new dietary ingredient — one “not marketed in the United States before October 15, 1994” — for which there was “inadequate information to provide reasonable assurance” that it does not present a significant or unreasonable risk of illness or injury when consumed by preterm infants.

One letter records that CFSAN had raised these safety concerns with the company at a meeting on 7 July 2023, questioning whether the clinical studies it cited “were robust enough to support safety, as the studies were short-term, poorly designed, and difficult to interpret without appropriate controls.” The letter adds that short-term clinical studies “have not served as the primary basis for safety in any GRAS conclusions to date for the use of living microorganisms.”

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6. The Two Warning Letters

• 28 September 2023 (letter 667715). Sent to the company selling the product named in the provider letter — the probiotic containing B. longum subsp. infantis linked to the infant death. The letter says the product was marketed for infants aged 0 to 36 months and was described as designed for infants in the NICU and “made specifically for use in healthcare settings.” The FDA found it to be an unapproved new drug and unlicensed biological product, and an adulterated food because its bacterium was an unsafe food additive when intended for preterm infants. The letter notes a further meeting with the company on 21 September 2023. According to the news release, the product “has since been voluntarily recalled and is no longer available in the U.S.”
• 24 October 2023 (letter 669353). Sent to a large nutrition-products manufacturer about a probiotic supplement containing B. infantis, S. thermophilus and B. lactis, offered to hospitals and promoted to NICU staff for preterm infants. The FDA found it to be an unapproved new drug, an unlicensed biological product and an adulterated dietary supplement (section 5). The letter notes that the product’s label said it was not intended for infants with compromised intestinal permeability, while other marketing materials directly contradicted that. The release states that this product “is not an infant formula,” and that the company “has agreed to discontinue sales” of it and was working with the FDA on further corrective actions.

Each letter asked the company to reply in writing within fifteen working days with the steps taken to correct the violations, and warned that failure to address them could lead to enforcement action such as seizure or injunction.

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7. What the FDA Said About the Evidence

The FDA documents do not say that probiotics have no effect in preterm infants. They describe the evidence as unsettled:

• The agency’s summary. The release says the FDA “understands there are conflicting data in the literature on the safety and effectiveness of probiotics for the prevention of necrotizing enterocolitis,” and that study has been “complicated by several factors, including the use of different probiotics in different trials.”
• The pediatricians’ position, as quoted. The provider letter quotes the American Academy of Pediatrics: “Given the lack of FDA-regulated pharmaceutical-grade products in the United States, conflicting data on safety and efficacy, and potential for harm in a highly vulnerable population, current evidence does not support the routine, universal administration of probiotics to preterm infants, particularly those with a birth weight of <1000 g.” That 2021 clinical report is listed under Key Research Papers.
• The call for trials. Citing the potential for harm, the agency “urges the industry, clinical and research funding communities to focus on high quality clinical trials with products meeting quality criteria,” both to inform clinical use and, where appropriate, to support drug and biologic applications “for use in infants of any age.”

Two officials were quoted in the release. The CBER director said that “products containing live microorganisms may present serious risks to preterm infants in hospital settings” and that, if used to prevent or treat disease, “they have not undergone the agency’s rigorous premarket process to evaluate their safety, effectiveness and quality for these medical uses.” The Deputy Commissioner for Human Foods, Jim Jones, said the agency was encouraging parents, caregivers and providers “to be aware of the possible risks associated with the administration of probiotic products to preterm infants in hospital settings.”

On reporting, the FDA asked healthcare providers and caregivers to report adverse events after probiotic use to the manufacturer, to the FDA’s MedWatch program (1-800-FDA-1088) and to CFSAN’s Adverse Event Reporting System, and noted that caregivers “may also speak with their healthcare provider regarding concerns or questions with these products.”

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8. What the Warning Does Not Do

• It is not about probiotics for healthy children or adults. Every document concerns preterm infants in hospital settings. The warning letters contrast preterm infants with “a healthy term infant population.”
• It is not a ban on probiotics. No regulation was issued and probiotic foods and supplements as a category were not prohibited. The findings apply to products sold to treat or prevent disease in preterm infants, or intended to be fed to them.
• It does not say probiotics never help preterm infants. The FDA acknowledged conflicting data and asked for high-quality trials (section 7).
• It does not bar research. The documents describe the IND route under which providers may give live microorganisms to treat or prevent disease with appropriate safeguards.
• It is not about infant formula. The release states that the second product “is not an infant formula.” The FDA’s separate 2023 formula steps are on the Infant Formula Safety page.

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9. Dates and Legal Status as of 18 October 2026

• 7 July 2023: CFSAN meets one company and raises safety concerns about use in preterm infants (per the 28 September warning letter).
• 21 September 2023: second meeting with that company.
• 28 September 2023: first warning letter issued.
• 29 September 2023: letter to healthcare providers.
• 24 October 2023: second warning letter issued.
• 26 October 2023: FDA news release announcing the warning and both letters.
• 25 September 2024: Federal Register notice of a public workshop (89 FR 78316).
• 25 October 2024: public workshop held; comments accepted until 25 November 2024.

Status as of 18 October 2026: a standing FDA safety warning, not a rule. The 2023 action consisted of a safety communication and two warning letters; it created no regulation that could be stayed or vacated. According to the release, one product was recalled and the other company agreed to stop selling its product. A check of the Federal Register from September 2023 through 18 October 2026 for FDA documents on necrotizing enterocolitis, probiotics in infants and live biotherapeutic products found only the 2024 workshop notice. No FDA approval of a probiotic product as a drug or biological product for infants was found.

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10. How the Warning Fits Later FDA Steps

The 2023 documents end with a call for better trials. The next FDA step found in the Federal Register is a notice published on 25 September 2024 (89 FR 78316, Docket No. FDA-2024-N-4392): the FDA, the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) announced a public workshop titled “Live Biotherapeutic Products to Prevent Necrotizing Enterocolitis in Very Low Birth Weight Infants.” Its stated purpose was “to exchange information with the medical and scientific community about the regulatory and scientific issues associated with use of live biotherapeutic products to prevent necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants.”

The warning also sits alongside other 2023 FDA actions on products for infants and on where supplement law ends: the 2023 infant formula safety letters, the public directory of supplement ingredients, and the finding that CBD does not fit food or supplement rules. A different 2023 action concerning preterm birth is reported on the preterm birth drug withdrawal page.

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11. Primary Documents

1. U.S. Food and Drug Administration, CBER and CFSAN (2023). Warning Regarding Use of Probiotics in Preterm Infants — Risk of Invasive Disease in Preterm Infants Given Probiotics Formulated to Contain Live Bacteria or Yeast. Dear Healthcare Provider letter, 29 September 2023 — fda.gov letter (PDF)
2. U.S. Food and Drug Administration (2023). FDA Raises Concerns About Probiotic Products Sold for Use in Hospitalized Preterm Infants. News release, 26 October 2023 — fda.gov news release
3. U.S. Food and Drug Administration, CBER and CFSAN (2023). Warning Letter, MARCS-CMS 667715, 28 September 2023. Published on fda.gov under Warning Letters (the address carries the company’s name and is not linked here).
4. U.S. Food and Drug Administration, CBER and CFSAN (2023). Warning Letter, MARCS-CMS 669353, 24 October 2023. Published on fda.gov under Warning Letters (the address carries the company’s name and is not linked here).
5. Food and Drug Administration, HHS (2024). Live Biotherapeutic Products To Prevent Necrotizing Enterocolitis in Very Low Birth Weight Infants; Public Workshop; Request for Comments. Notice. Federal Register 89:78316–78318, 25 September 2024. Docket No. FDA-2024-N-4392 — FR Doc. 2024-21928

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Key Research Papers

1. Esaiassen E, Cavanagh P, Hjerde E, Simonsen GS, Støen R, Klingenberg C (2016). Bifidobacterium longum subspecies infantis bacteremia in 3 extremely preterm infants receiving probiotics. Emerging Infectious Diseases 22(9):1664-1666 — PubMed PMID: 27532215
2. Bertelli C, Pillonel T, Torregrossa A, Prod’hom G, Fischer CJ, Greub G, Giannoni E (2015). Bifidobacterium longum bacteremia in preterm infants receiving probiotics. Clinical Infectious Diseases 60(6):924-927 — PubMed PMID: 25472946
3. Roy U, Jessani LG, Rudramurthy SM, Gopalakrishnan R, Dutta S, Chakravarty C, Jillwin J, Chakrabarti A (2017). Seven cases of Saccharomyces fungaemia related to use of probiotics. Mycoses 60(6):375-380 — PubMed PMID: 28133894
4. Pillai A, Tan J, Paquette V, Panczuk J (2020). Does probiotic bacteremia in premature infants impact clinically relevant outcomes? A case report and updated review of literature. Clinical Nutrition ESPEN 39:255-259 — PubMed PMID: 32859326
5. Poindexter B; Committee on Fetus and Newborn (2021). Use of probiotics in preterm infants. Pediatrics 147(6):e2021051485 — PubMed PMID: 34031231
6. Sharif S, Meader N, Oddie SJ, Rojas-Reyes MX, McGuire W (2023). Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database of Systematic Reviews 7(7):CD005496 — PubMed PMID: 37493095

The first four papers are the case reports cited in footnotes 1–4 of the FDA’s letter to providers; the 2017 report describes seven patients at two hospitals in India, two of them premature newborns and five adults. The 2021 paper is the American Academy of Pediatrics clinical report quoted in the same letter. The 2023 Cochrane review, published two months before the FDA letter, pooled 60 trials with 11,156 infants: it found low-certainty evidence that probiotics may reduce NEC in very preterm or very low birthweight infants, few data and possibly little or no effect in extremely preterm or extremely low birthweight infants, and its authors called for further large, high-quality trials.

PubMed Topic Searches

1. PubMed: probiotic bacteremia in preterm infants
2. PubMed: probiotics and necrotizing enterocolitis
3. PubMed: live biotherapeutic products in infants

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Connections

• FDA Actions of 2023
• FDA and Regulation
• Necrotizing Enterocolitis
• Neonatal Sepsis
• Preterm Labor
• Probiotics
• Probiotic Strains in Fermented Foods
• Infant Formula Safety Letters (2023)
• Preterm Birth Drug Withdrawal (2023)
• Dietary Supplement Ingredient Directory (2023)
• CBD Needs a New Regulatory Pathway (2023)

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