Probiotics not as effective in low-birth-weight neonates as trials indicate

Key takeaways:

• Probiotics in low-birth-weight infants reduced necrotizing enterocolitis but not sepsis or mortality.
• The effects were smaller than randomized controlled trial results would suggest.

A large study found that routine use of probiotics in neonatal ICUs reduced necrotizing enterocolitis but not mortality or sepsis in very-low-birth-weight infants, and the benefit was smaller than demonstrated by other studies.

According to Leila Agha, PhD, professor of health care policy at Harvard Medical School, and colleagues, only 123 of 745 American NICUs were routinely treating very-low-birth-weight infants with probiotics as of 2019.

“There have been more than 50 randomized clinical trials studying the use of probiotics for very-low-birth-weight infants,” Agha told Healio. “Meta-analyses of these trials have suggested sizable health benefits of probiotic use, including reductions in necrotizing enterocolitis, sepsis, and mortality. Despite this evidence, most U.S. NICUs do not routinely use probiotics.”

Agha said the new study “begins to unravel that puzzle by investigating whether the benefits of probiotics demonstrated in clinical trials materialize as probiotics diffuse into practice.”

Agha and colleagues retrospectively studied 307,905 infants with very low birth weight — defined as those weighing 1,500 g or less — in 807 NICUs in the Vermont Oxford Network of hospitals from 2012 through 2019. Over that time, the rate of probiotic treatment of neonates with very low birth weight rose from 4.1% in 2012 to 12.6% in 2019. The final analysis included 4,591 neonates with very low birth weight who received probiotics in 2019 at NICUs that adopted probiotic use.

The researchers found that NICUs that adopted probiotics did not experience reductions in sepsis (OR = 1.11; 95% CI, 0.98-1.25) or mortality (OR = 0.93; 95% CI, 0.80-1.08) that clinical trial evidence would have predicted. Adopting NICUs experienced an 18% reduction in the rate of necrotizing enterocolitis (OR = 0.82; 95% CI, 0.70-0.95) compared with NICUs that did not adopt the use of probiotics.

“This was a more modest reduction in necrotizing enterocolitis than we would have predicted based on clinical trial meta-analyses,” Agha said. “These findings raise important questions about why NICUs adopting probiotics are not experiencing the large health benefits documented in clinical trials.”

Agha mentioned two possible reasons that probiotics were not as effective in practice as they were in trials.

“One hypothesis is that infants exposed to beneficial bacteria for probiotics through vaginal delivery or breast milk might benefit less from probiotic supplementation,” Agha said. “But when we investigated this hypothesis in our data, we found the benefits of probiotics were similar, regardless of the infant’s delivery mode or whether the infant received breast milk.”

“Another hypothesis,” she said, “is that the probiotics used in trials may be different in their timing, dosing, or formulation. This is of particular concern because probiotics are marketed as dietary supplements, and thus are not FDA approved. A limitation of our analysis is that our data do not track the timing, dose, or formulation of the probiotics.”

She added that the paper suggests the “importance of evaluating the effectiveness of new treatments as they diffuse into routine practice.”

“There can be gaps between the efficacy of a treatment demonstrated in clinical trials, and the treatment’s effectiveness as it becomes widely used,” Agha said. “Uncovering these gaps can improve clinical understanding of the treatment and highlight important directions for future research.”

In an accompanying commentary, Matthew M. Davis, MD, MAPP, chair of the department of pediatrics and head of the division of general pediatrics and primary care at Lurie Children’s Hospital of Chicago, said the study “offers a welcome focus on potential mortality benefit for infants born at very low birth weight.”

“As a group, infants have a higher mortality rate than older children, adolescents, and adults younger than age 55 years in the U.S. — a reminder of the vulnerability of the youngest young — and the mortality risk for infants with [very low birth weight] is several times higher than for infants of normal birth weight,” Davis wrote.

Davis applauded the choice to focus on probiotics as an intervention to reduce mortality.

“To reverse the latest declines in life expectancy in the U.S., more research must be conducted with population-level mortality as the primary outcome,” Davis wrote. “Such a focus may seem dated in an era when the U.S. has improved survival for many diseases compared with a generation ago. However, the recent declining life expectancy in the U.S. reflects concerning external and internal patterns.”

“The current mortality burden falls disproportionately on population subgroups who have not fully experienced the benefits of biomedical research and for whom a concentrated prioritization on mortality reduction could have a tremendously positive impact while also improving life expectancy of the whole population,” he wrote.

References:

Agha L, et al. JAMA Health Forum. 2023;doi:10.1001/jamahealthforum.2023.0960.

Davis MM, et al. JAMA Health Forum. 2023;doi:10.1001/jamahealthforum.2023.0166.