Loren Bonner
For years, clinicians in hospital NICUs have been giving preterm infants probiotic products to prevent a life-threatening illness called necrotizing enterocolitis, which causes tissues in the lining of their bowels to become inflamed and die. The mortality rate associated with necrotizing enterocolitis is as high as 50%, but the condition can also lead to serious infection, long-term disability, and developmental problems.
In a new warning, FDA advised health care providers to stop giving preterm infants probiotic products, which are not FDA-regulated, due to the bacteria and fungi found in probiotics that might put preterm infants at risk of invasive and potentially fatal infections.
The warning comes on the heels of a preterm infant’s death. Through an FDA investigation, genomic sequencing data found the bacterium that caused sepsis in this infant was a genetic match to the bacteria contained in the commercial probiotic product Evivo with MCT Oil (Infinant Health). FDA sent warning letters to Infinant Health, which voluntarily recalled their product, as well as to Abbott Laboratories for its product Similac Probiotic Tri-Blend. Abbott has agreed to discontinue sales of Similac Probiotic Tri-Blend and is working with FDA to take additional corrective actions.
“We want to warn parents, caregivers, and health care providers that if these products are used for the prevention or treatment of disease, they have not undergone the agency’s rigorous premarket process to evaluate their safety, effectiveness, and quality for these medical uses,” said Peter Marks, MD, PhD, director of FDA’s Center for Biologics Evaluation and Research, in an FDA statement.
But what are health care providers supposed to do without an alternative?
Trials are underway for an FDA-approved probiotic product for preterm infants, but the timeline to market is not clear.
The literature
“Necrotizing enterocolitis is so devastating, and multiple factors are thought to be the cause, including overgrowth of intestinal bacteria,” said Jamie Miller, PharmD, from the University of Oklahoma College of Pharmacy. She said hospitals seem split on using probiotics or not using them to prevent necrotizing enterocolitis.
Several studies have shown the benefit of probiotics in preventing the condition. Some institutions adopted the practice when there was a big push for it years ago. The main concern, as FDA has stated, is the risk of sepsis and the fact that the products are not regulated.
“Meta-analyses have shown definite benefit,” said Miller, who also practices at Oklahoma Children’s Hospital OU Health. Her institution decided not to administer probiotics to preterm infants. “The issue is it’s just not a regulated product,” she said. When the topic came up a while back at Oklahoma Children’s, they did have one probiotic on their formulary, but it was not one that showed a benefit for prevention of necrotizing enterocolitis. “That’s the other thing: you have to determine if the probiotic on formulary is one that has been shown to be beneficial. Having an FDA-regulated product would help things considerably,” said Miller.
Probiotics are added to milk feeds and Miller said there were also practical issues using it, including dosing.
A July 2023 meta-analysis in Cochrane Review which involved 60 trials and roughly 11,000 preterm infants concluded that giving preterm infants probiotics, compared with giving them placebo or no treatment, may reduce their risk of necrotizing enterocolitis and probably decreases an infant’s risk of death. However, researchers said most trials included in the analysis were small and had design flaws that might have biased the findings and that there is a need for further large, high-quality trials to inform policy and practice.
An analysis published in JAMA Pediatrics from October 2023 of more than 100 studies and roughly 25,000 preterm infants found that probiotics containing multiple strains of bacteria were associated with reduced necrotizing enterocolitis and deaths.
“FDA understands there are conflicting data in the literature on the safety and effectiveness of probiotics for the prevention of necrotizing enterocolitis, and that the study of the use of probiotics has been complicated by several factors, including the use of different probiotics in different trials,” FDA said in a statement.
According to a 2021 report from the American Academy of Pediatrics (AAP), three of the earliest randomized trials of probiotics in preterm infants suggesting benefit were conducted outside the United States. The authors noted that the studies are hindered by methodological differences among study protocols, including different strains and combinations of therapy. Different countries have different organism strains.
“It is not clear whether it is appropriate to pool data from trials by using different strains of probiotics, leading many investigators to urge caution in interpretation of meta-analyses of probiotics for the prevention of morbidity in preterm infants,” the authors of the AAP report wrote.
Which way forward?
The AAP report from 2021 stressed that clinicians should not use probiotics until there’s an FDA-regulated product to ensure that the preparations are appropriate. Even after this warning, many hospitals continued the practice. Miller thinks the FDA warning, however, could have a stronger impact since institutions won’t want to be liable if something happens. ■