For the second time in the past few weeks, a new study out of Europe has found that use of probiotics may improve outcomes in premature infants.
The study, published yesterday in JAMA Network Open, found that daily supplementation with a multistrain probiotic formula in a cohort of premature infants in Sweden was associated with a lower risk of death and/or necrotizing enterocolitis (NEC) compared with those who didn’t receive the probiotic formula.
NEC is a severe gastrointestinal disease that occurs when there’s a microbial imbalance and loss of beneficial bacteria in the gut, which can result in the overgrowth of pathogenic bacteria. It’s a major cause of illness and death in preterm infants.
In a study published late last month in the same journal, researchers reported the routine use of the same multistrain formula in premature infants in the Netherlands cut the incidence of NEC in half compared with those who didn’t receive the formula, though there was no difference in all-cause mortality between the two groups.
The formula used in both studies contains Bifidobacterium infantis Bb-02, Bifidobacterium lactis BB-12, and Streptococcus thermophilus TH-4 and is conditionally recommended by the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) for reducing NEC rates.
Both studies add to a growing body of literature indicating that specific probiotic strains reduce NEC incidence in preemies.
A favorable benefit-risk profile
In the new study, a team led by researchers from Sweden’s Karolinska Institutet examined data from the Swedish National Quality Registry on premature infants admitted to 38 neonatal intensive care units (NICUs) from 2017 through 2024. They focused on infants born from 28 weeks to 31 weeks, who were classified as “very preterm.”
In 2020, the Swedish Neonatal Society issued a national recommendation to provide probiotics to very preterm infants, based on the ESPGHAN recommendation.
“Implementation after this nationwide recommendation provides an opportunity to evaluate associations between probiotic supplementation and death, NEC, and sepsis in a population-based setting in which exposure and outcome data were prospectively recorded in a national register,” the study authors wrote.
Of the 4,695 infants (mean age, 30.2 weeks; 54.3% male) included in the study, 1,571 were in the probiotics group, and 3,124 were in the no probiotics group. Probiotic use in the 38 NICUs rose from 0% before the national recommendation (2017 through 2019) to 65% from 2021 through 2024.
When comparing the periods before and after the national recommendation, the researchers found that the overall rate of the composite outcome of death and/or NEC declined from 3.4% to 1.5%. Probiotic supplementation versus no supplementation was associated with a 72% lower risk of death and/or NEC (rate, 0.8% vs 3.4%; adjusted relative risk [ARR], 0.28).
Families should be informed about this positive benefit-risk profile.
When assessed separately, the risk of death (rate 0.3% vs 1.4%; ARR, 0.16) and NEC (rate, 0.6% vs 2.5%; ARR, 0.25) were both significantly lower in the infants who received probiotics.
Importantly, probiotic supplementation was not associated with increased risk of death or sepsis (rate, 3.4% vs 4.4%; ARR, 0.86). Rare cases of probiotic-associated sepsis are among the safety concerns that have been raised about probiotic supplementation in premature infants.
“Regarding probiotic-associated sepsis, no cases during the implementation period were reported when we surveyed Swedish NICUs, which is reassuring and supports the safety of this strategy,” the authors noted.
While “ongoing vigilance” for safety issues remains warranted, the researchers say, the findings support a favorable benefit-risk profile for probiotic supplementation in very preterm infants.
“Families should be informed about this positive benefit-risk profile,” they wrote.
Limited use in the United States
The rate of probiotic uptake observed in the Swedish NICUs after the national recommendation is similar to that of other countries, according to the study. In Canada, uptake in infants born before 34 weeks was 67% in 2022; in England and Wales, it was 54% in 2022.
But in the United States, it’s a different story. A study conducted in 807 US NICUs found that only 17% had adopted routine probiotic use by 2019. In 2021, the American Academy of Pediatrics cautioned against the routine use of probiotics in infants weighing less than 2.2 pounds, citing mixed data on efficacy, potential harms, and the fact that probiotics are considered a dietary supplement in the United States and therefore lack Food and Drug Administration (FDA) approval for the treatment or prevention of disease.
Use of probiotics in premature infants then dropped dramatically after the FDA issued a warning to healthcare providers in September 2023 about the risk of probiotics after a preterm infant died of sepsis following administration of a single-strain probiotic (Evivo with MCT Oil).
A study earlier this year in the Journal of Perinatology found that after the FDA warning in 2023, NEC incidence increased at US NICUs where use of probiotics was high.
One can hope that these findings stimulate other countries and clinicians to take a more rational approach to the use of probiotics and live biotherapeutics in preterm infants.
The NEC Society, a nonprofit group representing families who’ve been affected by the condition, notes on its website that despite supporting evidence, “the protective benefits of probiotics remain inaccessible to preemies in the United States.”
“It has been nearly three years, and more premature infants in the US are dying as families wait for an FDA-approved, live biotherapeutic product for NEC,” the group said.
In an accompanying commentary, Ravi Patel, MD, MSc, of Emory University School of Medicine and Children’s Healthcare of Atlanta, says the experience in Sweden, where evidence-based national guidelines and recommendations have led to a rapid increase in probiotic use in NICUs, “stands in stark contrast to the concerning situation in the US.”
“The study…provides additional evidence of probiotic effectiveness and how national implementation can dramatically reduce the burden of NEC, potentially improve survival, and achieve improvements that many countries around the world would be excited to see in their NICUs,” he wrote. “One can hope that these findings stimulate other countries and clinicians to take a more rational approach to the use of probiotics and live biotherapeutics in preterm infants.”
