Federal health agencies should expedite reviews and trials of live biotherapeutic products, commonly referred to as probiotics, used to improve the health and outcomes of infants with low birth weight, the chair of the AAP Section on Neonatal-Perinatal Medicine (SONPM) told government officials during a recent workshop.
While studies on the effectiveness of probiotics in preterm infants have had mixed results, providers have used the products to help reduce mortality, improve feeding tolerance, reduce the duration of hospitalization and prevent necrotizing enterocolitis (NEC), a leading cause of illness and death among preterm infants.
The Oct. 25 workshop provided information on the regulatory and scientific issues associated with use of probiotics to prevent NEC. The meeting was hosted by the Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH).
In 2023, the FDA sent a letter to health care providers warning of the risk of using products containing live bacteria or yeast (probiotics) in preterm infants in hospital settings. The warning said infants who are given probiotics are at risk of invasive, potentially fatal disease caused by bacteria or fungi contained in probiotics. It also referenced the 2021 AAP policy statement Use of Probiotics in Preterm Infants, which said "current evidence does not support the routine, universal administration of probiotics to preterm infants, particularly those with a birth weight of <1000 g." The FDA has not approved any probiotic product for use as a drug or biological product in infants.
Pediatricians have expressed concern that the FDA warning may result in harm to a fragile patient population.
During the workshop, SONPM Chair Munish Gupta, M.D., FAAP, said misunderstandings may have resulted from the FDA letter.
The reference to AAP policy in ”the 2023 warning may leave the misimpression that the AAP opposes all use of probiotics in preterm infants,” said Dr. Gupta, director of quality improvement at Beth Israel Deaconess Medical Center and an assistant professor at Harvard Medical School. “While the warning appropriately highlighted the statement’s conclusion that ‘current evidence does not support the routine universal administration of probiotics for preterm infants,’ it does not address other key components of that statement. The statement acknowledges some centers may choose to administer probiotics and offers guidance for how this can be done appropriately.”
Members of SONPM have reported some neonatal intensive care units (NICUs) have stopped using probiotics, Dr. Gupta said.
“The unmistakable result of the warning has been a large reduction in the use of probiotics in NICUs,” Dr. Gupta said. “We respect and appreciate FDA regulatory oversight, and we know this supervision is essential for safe health care in the United States. However, neonatologists are struggling to navigate this decision.”
The public workshop is just one effort to identify the cause of NEC, which CDC data showed was responsible for the deaths of 356 infants in 2022. Earlier this year, juries ordered Abbott and another specialty formula manufacturer to pay millions of dollars in damages claiming the companies failed to warn families about the risk of NEC.
The FDA, CDC and NIH released a consensus statement in October that stated there is no conclusive evidence that specialty formulas for preterm infants cause NEC. Rather, evidence supports the hypothesis that the absence of human milk is associated with an increased risk of NEC.
Dr. Gupta said several reviews have found significant reductions in NEC and mortality among preterm infants given probiotics.
“While the overall certainty of evidence is mixed and the optimal dose and formulation remain unknown, the likelihood that probiotics contribute to positive outcomes in preterm infants seems high,” he said.
The FDA letter included a reminder that health care professionals are required to submit an investigational new drug (IND) application to the agency prior to using probiotics in this patient population.
“Asking individual NICUs to pursue an IND is not realistic for our members,” Dr. Gupta said. “We urge the FDA and others to work with the scientific community and manufacturers to expedite trials and review of these products as much as possible. Perhaps, innovative study designs can be used that facilitate the participation of many NICUs and can thus help obtain the needed evidence more quickly.”
Dr. Gupta said the guidelines in the AAP policy statement could be used as criteria to allow some flexibility in the FDA process and allow greater access to probiotics to promote overall intestinal health and improved outcomes for the most fragile premature infants.
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