- Probiotics given to preterm infants have been shown to reduce the risk of necrotizing enterocolitis, death, and late-onset invasive infection, but concerns persist about the risk of sepsis from probiotic organisms.
- In a retrospective cohort study of over 100,000 very preterm infants, 11 developed Bifidobacterium or Lactobacillus invasive infections, eight of whom were given probiotics and three who were not.
- Probiotic supplementation was associated with an absolute increase of 0.04% in Bifidobacterium or Lactobacillus infection, equivalent to one invasive infection per roughly 2,500 supplemented infants.
Probiotic-associated invasive infections were rare in very preterm infants, according to a large retrospective cohort study.
Among over 100,000 very preterm infants, 11 developed Bifidobacterium or Lactobacillus invasive infections. Eight had been given probiotics (0.04%) while three had not (0.003%), reported Ravi Mangal Patel, MD, MSc, of Emory University School of Medicine and Children’s Healthcare of Atlanta, and colleagues.
In overall unmatched and propensity-matched analyses, probiotic supplementation was associated with an absolute increase of 0.04% in Bifidobacterium or Lactobacillus infection (95% CI 0.01-0.06), equivalent to one invasive infection per roughly 2,500 supplemented infants (95% CI 1,667-10,000), they wrote in a research letter in JAMA Network Open.
Probiotics given to preterm infants have been shown to reduce the risk of necrotizing enterocolitis, death, and late-onset invasive infection, Patel and colleagues explained. “Despite benefits, valid concerns exist about the risk of sepsis from probiotic organisms.”
“Our findings provide clinicians, researchers, families, and regulators with a more reliable estimate of the risk of probiotic-associated invasive infection in preterm infants cared for in U.S. NICUs [neonatal intensive care units],” Patel told MedPage Today in emailed remarks. “That risk appears to be very low.”
The authors pointed out that their study “allowed for quantification of uncommon risks, and consistent findings in propensity-matched results that considered confounding by indication based on baseline factors, including GA [gestational age] and birth weight, were reassuring.”
They also noted that their results were consistent with those from a large retrospective cohort study in Canada.
However, probiotic-associated sepsis has been reported in case series and case reports, including a systematic review of 16 studies involving 32 preterm infants. “The isolated organisms were consistent with the most administered probiotic products in preterm infants, including Bifidobacterium and Lactobacillus strains, with genomic analysis confirming the probiotic as the source,” Patel and team wrote.
In 2023, the FDA issued a warning based on a case report that detailed the risk of invasive disease in preterm infants who were administered probiotics. To date, “absolute risks of probiotic-associated sepsis remain uncertain given the lack of large cohort studies systematically estimating uncommon risks,” the authors said.
In an accompanying commentary, Brian Scottoline, MD, PhD, and Brian K. Jordan, MD, PhD, both of Oregon Health & Science University in Portland, wrote that the “risk-benefit profile of probiotics in [very low birth weight] infants for reducing NEC [necrotizing enterocolitis] incidence and death due to NEC appears substantially weighted in favor of live bacterial products.”
“Large trials and, if approved as a drug, patient surveillance could help refine the risk data,” they added. “Paraphrasing Jennifer Canvasser, parent of an infant who succumbed to NEC and founder of the NEC Society, these results highlight the relatively uncommon risks of probiotic bloodstream infection in preterm neonates compared with the overwhelmingly more common risk of NEC.”
For this study, Patel and colleagues used the Pediatrix Medical Group Clinical Data Warehouse, a multicenter dataset that is prospectively collected and used by NICUs in 33 states and Puerto Rico.
They evaluated 107,505 very preterm infants with a median gestational age of 30 weeks; 47% were girls, and 27% had a birth weight of less than 1,000 g.
Of these infants, 19% were administered probiotic supplementation. Median gestational age and birth weight were numerically similar among infants who were given probiotics and those who were not.
Among 613 deaths in infants receiving supplementation, just one occurred more than 30 days after positive blood culture in an infant with invasive infection.
Limitations included the inability to perform bacterial genomic analysis to determine causality due to the study’s retrospective nature, Patel and colleagues noted. Also, while they evaluated the two most common bacteria contained in probiotics given to preterm infants, all bacteria, yeast, or contaminants in every probiotic product might not have been captured.
“Given the infrequent incidence of invasive infection, very large cohorts may be needed to quantify such rare risks,” the authors wrote.
The hope is that the current data “will help clinicians and families make more informed decisions and will also be useful to the FDA and other regulators as they consider how probiotics and live biotherapeutic products should be evaluated and safely used in the NICU,” Patel said.
