Premature infants who receive probiotics may have a reduced risk of developing necrotizing enterocolitis (NEC) and dying, according to a large Swedish study that adds to evidence supporting the use of live microorganisms in this population.

The findings come as US neonatologists continue to navigate conflicting evidence and regulatory concerns surrounding probiotics in the NICU.

“The use of probiotics early in life can prevent NEC, as these beneficial bacteria favorably alter the community and protect the bowel from being compromised by pathologic bacteria,” said Jae Kim, MD, neonatologist and co-director of the Perinatal Institute at Cincinnati Children’s Hospital Medical Center in Cincinnati, Ohio, who was not involved in the study.

A healthy microbiome in infants is associated with improved immune function, intestinal barrier function, and motility, he said. NEC occurs predominantly in premature infants, whose immature intestines are associated with an abnormal gut.

The FDA has warned that premature infants given probiotics are at risk for invasive, potentially fatal infections. The agency has not approved any probiotic as a drug or biological product for infants, so the products are not widely used in hospitals in the US.

Large Reduction in NEC

The study, published in JAMA Network Open, found that Swedish infants born between 28 and 31 weeks of gestation who were given probiotic supplementation had lower risks of developing NEC (absolute relative risk [ARR], 0.25; 95% CI, 0.10-0.61) and death (ARR, 0.16; 95% CI, 0.06-0.45).

The Swedish researchers used data from the country’s national neonatal quality registry of infants born between 2017 and 2024. Sweden’s national neonatal society recommended probiotic supplementation for very premature infants in 2020, creating a basis for analyzing outcomes before and after the practice was widely implemented. Baseline characteristics of infants in the two groups were similar.

The probiotic regimen consisted of three bacterial strains — Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus — administered once daily beginning before day 4 of life and discontinued at postmenstrual week 34.

Of the more than 4600 infants, roughly one third received probiotics. Deaths during the first 3 days of life were excluded, before infants would generally have been exposed to probiotics.

NEC occurred in 0.6% vs 2.5% of infants who received probiotics vs who did not, while death occurred in 0.3% and 1.4%, respectively.

The researchers also found infants who received probiotics had a lower risk for surgical NEC (ARR, 0.04; 95% CI, 0.01-0.21). Up to 50% of babies with NEC need an operation to remove perforated or dead tissue.

“After 2020, infants who did not receive probiotics had approximately the same rate of death or NEC as infants born before the guideline was introduced, whereas those who received probiotics had a substantially lower rate,” said Ayoub Mitha, MD, PhD, neonatologist and researcher at the Karolinska Institutet in Stockholm, Sweden, who led the study. “This makes a general improvement in care over time a less likely explanation.”

The study results echo previous studies suggesting that probiotics, particularly multistrain preparations, can reduce NEC in premature infants. A 2025 review of 60 trials involving more than 11,000 infants reported a 46% lower risk for NEC with probiotics.

The Swedish study’s accompanying editorial raised the possibility of immortal time bias. Infants had to survive long enough to receive the intervention, potentially making the probiotic group appear to have a lower mortality risk.

“Residual immortal time bias cannot be completely excluded and may have contributed to the magnitude of the observed association with mortality,” Mitha said.

The Swedish infants were predominantly fed human milk and received a specific three-strain probiotic preparation. Those factors limit how broadly the findings can be applied.

“One should be cautious to extrapolate our findings to other probiotic strains, populations, and contexts,” Mitha said.

What Does This Mean for US NICUs?

In 2021, the American Academy of Pediatrics (AAP) said available evidence did not support routine, universal probiotic administration to premature infants, particularly those weighing < 1000 g at birth. The AAP cited differences among products and trials, conflicting safety and efficacy data, and the absence of an FDA-regulated pharmaceutical-grade probiotic product in the US.

The FDA in 2023 sent letters to clinicians warning them of Bifidobacterium longum sepsis after one premature infant died after being administered a probiotic product. The agency reported more than two dozen adverse events in the US since 2018 associated with certain probiotic products.

“This led to a dramatic reduction in probiotic use, including the three-strain versions used in Sweden,” Kim said.

In the study, culture-proven late-onset sepsis occurred at roughly the same rate between groups. They also surveyed all Swedish NICUs during this study, with none reporting cases of probiotic-associated sepsis.

Kim said the regulatory environment has had a substantial effect on probiotic use in US NICUs.

“Most neonatologists are convinced that we should be using probiotics to reduce NEC and all-cause mortality,” said Kim. “The barrier for individual units changing their practice is the risk of going against current standard of care that avoids probiotics until we have an FDA-approved product.”

A single-agent probiotic supplement made by Infant Bacterial Therapeutics (IBT) is currently under FDA review.

“If this gets approved, the NICU community will be able to begin using probiotics again,” said Kim, who serves as a consultant for IBT. “In the future, there may be opportunities to revisit the benefits of three-strain products, but this will take more clinical study and approval time.”

Kim reported serving as a consultant for IBT and working with several probiotic manufacturers in the past. Mitha reported having no relevant disclosures. Other study authors reported receiving consultation fees, research support, and grants from Danone Nutricia, Intertek Health Sciences Inc., and the Swedish Research Council. One study author reported being the co-founder of Neobiomics AB, which manufactures the probiotic product used in the research.

Lara Salahi is a health journalist based in Boston.