Last fall, the FDA issued a warning letter ordering two manufacturers to stop selling probiotic products for use in preterm infants. This has put the agency at odds with some physicians who worry about the harm of not using these products in this vulnerable population.
Clinicians across the country had relied on specific probiotic products for reducing the risk for necrotizing enterocolitis (NEC) and death in preterm infants—an intervention supported by efficacy and safety data from more than 60 trials in over 11,000 infants (Cochrane Database Syst Rev 2023;7[7]:CD005496). Taken together, the data motivated the use of probiotics in approximately 40% of U.S. NICUs and nearly all NICUs in some countries, including Canada, Switzerland and New Zealand (Children [Basel] 2023;10[12]:1889).
Across these trials, sepsis was a rare but well-known serious adverse event associated with probiotic administration (Gastroenterology 2020;159[2]:467-480). A fatal case of sepsis in a preterm infant who received a product containing Bifidobacterium longum subsp. infantis with medium-chain triglyceride oil was what prompted the FDA to issue the warning letter to healthcare professionals. The agency maintains that probiotics, as dietary supplements, do not meet the same rigorous study and manufacturing standards as a drug and, therefore, are illegal when used in the context of disease treatment, mitigation, cure or prevention.
Subsequently, the FDA called on two manufacturers of probiotics for preterm infants to stop selling their products. Both companies complied and discontinued sales. Even in Canada, where probiotics are regulated under a different framework, one product that healthcare professionals commonly used for preterm infants was quietly taken off the market after the FDA warning.
Physicians Say Benefits Outweigh Risk
In contrast to the FDA’s stance that “products containing live microorganisms may present serious risks to preterm infants in hospital settings,” many physicians find the probiotic data sufficiently compelling that they are more concerned about the harm of not providing these products to this vulnerable group of patients. A recent Cochrane analysis calculated probiotics’ number needed to treat as 33.
Nikhil Pai, MD, CNSC, a pediatric gastroenterologist at McMaster Children’s Hospital and an associate professor at McMaster University, in Hamilton, Ontario, told Gastroenterology & Endoscopy News that despite some low-quality probiotic trials and variability in results, the sheer number of studies that have shown benefits for preterm infants in different settings is meaningful, especially for preventing the worst outcomes of such a common and devastating condition as NEC.
Mark Underwood, MD, MAS, a neonatologist and an emeritus professor of pediatrics at UC Davis School of Medicine, who has led multiple probiotic trials in neonates, was surprised by the timing of the regulatory warning. He said the short-term consequence of the FDA’s announcement appears to be an abrupt reduction in physicians suggesting probiotics to parents of preterm infants throughout the United States. With the reduction in product availability, he said many NICUs have now put a stop to routine probiotic use. However, these products continue to be administered at centers conducting FDA-approved clinical trials in preterm infants.
At his practice in Spokane, Wash., Dr. Underwood’s approach with parents of preemies has changed since last year’s FDA alert. He told Gastroenterology & Endoscopy News that he now shares the FDA warning with parents. “I say the FDA has never approved these products, and they’re not likely to until a product is marketed that meets their investigational new drug oversight.” He then discusses the risks and benefits associated with probiotic use.
Dr. Underwood called the current situation a “catch-22” and doubts whether in the near future any dietary supplement company will invest the tens of millions of dollars necessary to advance a product through drug trials with no guarantee of eventual success.
Recognizing the potential concerns surrounding the use of the agents, Andi L. Shane, MD, MPH, MSc, and Geoffrey Preidis, MD, PhD, described “a strategy to address [the risk] by improving testing standards for probiotic products” in a July 2023 Viewpoint article in JAMA Pediatrics (2023;177[9]:879-880). They recommended a framework that includes use of products manufactured under more stringent pathogen testing standards with third-party verification, “procedures to avoid extrinsic contamination” and postmarket monitoring. They acknowledged the financial implications of such an approach, but wrote that it would be “an investment that would enhance selection of the optimal probiotic products for specific clinical scenarios.”
Concerns About Downstream Effects
It remains to be seen whether the FDA would reconsider use of probiotics under such a framework. In the meantime, if NEC rates begin to increase, Dr. Pai predicted that pediatric gastroenterologists may encounter more and more children with short bowel syndrome, which in infancy usually is caused by NEC. Yet for him, the possible increase in preterm infant mortality is an even bigger concern. “The more ominous outcome is the patients we don’t see,” he said.
Dr. Pai also pointed out the advantages of NEC prevention over treatment. Children who develop NEC often receive lifesaving antibiotics, but large population studies show these early-life antibiotics come with a risk for chronic conditions such as obesity and inflammatory bowel disease later in life (Front Endocrinol 2017;8:170; Gut 2023;72[4]:663-670).
He also said he hopes the FDA’s approach doesn’t extend to probiotic use in gastroenterology as a whole. Despite some probiotics showing efficacy for certain GI-related end points in clinical trials, the fact that no products have gone through the rigorous testing necessary to qualify as drugs would limit physicians to informing patients about general benefits, such as gut health.
—Kristina Campbell
This article is from the May 2024 print issue.