Probiotic Use in NICUs Shows Some Benefits in Newborns With Very Low Birth Weight

Routine use of probiotics among newborns with very low birth weight in U.S. neonatal intensive care units (NICUs) was associated with a lower risk of necrotizing enterocolitis, but not sepsis or mortality, according to a cohort study.

Among over 300,000 newborns, the incidence of necrotizing enterocolitis was reduced by 18% at NICUs that adopted use of probiotics (OR 0.82, 95% CI 0.70-0.95, P=0.10) compared with non-adopting NICUs, reported Leila Agha, PhD, of Harvard Medical School in Boston, and colleagues.

However, adoption of probiotics was not associated with a significant reduction in sepsis (OR 1.11, 95% CI 0.98-1.25, P=0.09) or mortality (OR 0.93, 95% CI 0.80-1.08, P=0.33), they noted in JAMA Health Forum.

"These findings highlight the importance of monitoring the effectiveness of probiotics as they diffuse into neonatal practice beyond the setting of clinical trials," Agha's group wrote.

Of note, the rate of probiotic use in neonates with very low birth weight increased from 4.1% in 2012 to 12.6% in 2019, but still only 16.5% of NICUs had begun this practice by 2019. Of those that had, 76.3% of newborns received probiotics in 2019.

Slow adoption of the use of probiotics may be due to uncertainty about the quality of commercially available probiotic products, Agha and team said. Probiotic products and their production are not regulated by the FDA.

While the incidence of necrotizing enterocolitis has decreased, they noted, affected babies remain at high risk for death, neurodevelopmental disabilities, repeated surgeries, and long-term tube feeding.

Three previous meta-analyses including 30 to 56 randomized clinical trials evaluated the use of enteral probiotics among infants with very low birth weight, finding that their use was associated with a 43% to 45% reduction in necrotizing enterocolitis, an 11% to 14% reduction in sepsis, and a 23% to 24% reduction in mortality, which led to calls for widespread adoption across NICUs.

However, sensitivity analyses found more modest changes in necrotizing enterocolitis, and no significant associations with sepsis or mortality, Agha and team said.

"When a large-scale analysis of patient outcomes in a clinical setting such as the study by Agha and colleagues does not confirm the full span of findings observed in more controlled environments with smaller samples, it is appropriate to ask questions," noted Matthew M. Davis, MD, of Northwestern University Feinberg School of Medicine in Chicago, in an accompanying editorial.

Such questions include whether the NICUs used probiotics the same way they had been used in clinical trials that showed reductions in sepsis and mortality and whether there were fundamental differences among the products used in different locations, he added.

For this study, Agha and team used data from the Vermont Oxford Network, which is estimated to include data on more than 85% of infants born with very low birth weight -- defined by the NIH as weighing under 1,500 g -- in the U.S. They included 307,905 neonates at 807 NICUs from January 2012 through December 2019. Mean gestational age was 28.4 weeks, and 50% were boys.

The researchers defined probiotic use as formulas containing probiotics or probiotic supplements added to formula or breast milk.

They conducted a difference-in-differences analysis that compared changes in outcomes among infants with very low birth weight between adopting and non-adopting NICUs before and after hospital adoption of probiotics.

Agha and colleagues noted that probiotics provided smaller benefits for infants with extremely low birth weight compared with those with very low birth weight. The association of probiotic use with neonate outcomes was not significantly different for those who were delivered vaginally or via cesarean section or for those who received breast milk and those who didn't.