From the AGA Journals

Combination probiotic formulations might improve outcomes in preterm infants

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Probiotics have limited evidence of harm and significant evidence of benefit in NEC

The demonstration of decreased risks of both death and necrotizing enterocolitis (NEC) in randomized placebo-controlled trials of probiotic microbes in very preterm babies is the most compelling case for administration of probiotics to date. Questions remain, including the optimal probiotic microbe(s) and dose for this population. The ideal studies would compare commercially available probiotic products and doses to each other (rather than to placebo). In the absence of these ideal studies, a network meta-analysis is a valuable tool to compare and rank multiple treatments. One of the drawbacks of a network meta-analysis is the assumption that all interventions have similar effects in all populations (an assumption that is challenging given the marked differences in the incidence of NEC between hospitals and populations).

The study conclusion that the combination of at least one Lactobacillus strain and at least one Bifidobacterium strain is most effective in preventing both death and NEC in very preterm infants is consistent with a previous network meta-analysis and with recent recommendations of the European Society for Paediatric Gastroenterology Hepatology and Nutrition and the American Gastroenterological Association.

Dr. Mark A. Underwood is a professor of pediatrics and neonatology at University of California at Davis

Dr. Mark A. Underwood

Administration of probiotics to very preterm infants remains uncommon in many countries, including the United States. Parents of infants with NEC commonly express frustration at the lack of information about this disease and available preventive strategies. Given an intervention with limited evidence of harm and significant evidence of benefit, it is incumbent upon neonatologists to discuss the available evidence with parents and include their wishes in the decision-making process.

Mark A. Underwood, MD, MAS, is a professor of pediatrics and chief of the division of neonatology in the department of pediatrics at the University of California, Davis. He has received honoraria from Abbott and conducted a clinical trial of probiotics that was funded by Evolve Biosystems.



For preterm, low-birth-weight infants, probiotic formulations containing Lactobacillus and Bifidobacterium strains appear to be superior to single-strain probiotics and to other multiple-strain formulations for reducing the risk of all-cause mortality, according to the findings of a network meta-analysis of randomized clinical trials.

The results of a prior Cochrane review indicated that probiotics can help prevent severe necrotizing enterocolitis and all-cause mortality in preterm infants, but the most effective formulations remained unclear. Therefore, Rebecca L. Morgan, PhD, MPH, and her associates searched MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, BIOSIS Previews, and Google Scholar through Jan. 1, 2019, to identify studies of single-strain and multistrain probiotic formulations in preterm, low-birth-weight neonates. A total of 63 studies involving 15,712 infants met inclusion criteria. “We used a frequentist approach for network meta-analysis and [a] GRADE approach to assess certainty of evidence,” they noted.

“High-certainty” evidence indicated that combination therapy with one or more Lactobacillus species and one or more Bifidobacterium species significantly reduced all-cause mortality, compared with placebo (odds ratio, 0.56; 95% confidence interval, 0.39-0.80), wrote Dr. Morgan, of McMaster University, Hamilton, Canada, and her coinvestigators. This was the only intervention to have moderate- or high-quality evidence for a reduction in mortality, the researchers wrote in Gastroenterology.

They added that, among the probiotic formulations with moderate- or high-quality evidence for efficacy, compared with placebo, those containing at least one species of Lactobacillus and at least one species of Bifidobacterium, and the single-strain probiotics containing Bifidobacterium animalis subspecies lactis, Lactobacillus reuteri, or Lactobacillus rhamnosus significantly reduced the risk of severe necrotizing enterocolitis (Bell stage II or higher), with statistically significant odds ratios of 0.35, 0.31, 0.55, and 0.44, respectively.

Three formulations were associated with “low-” or “very low-certainty” evidence for a reduction in risk for severe necrotizing enterocolitis, compared with placebo: Bacillus plus Enterococcus species, Lactobacillus plus Bifidobacterium plus Enterococcus species and Bifidobacterium plus Streptococcus salivarius subspecies thermophilus. Estimated odds ratios were 0.23 (risk difference, –4.9%), 0.28 (RD, –4.9%), and 0.38 (RD, –3.9%), respectively.

“The combinations of Bacillus species and Enterococcus species, and one or more Bifidobacterium species and S. salivarius subspecies thermophilus, might produce the largest reduction in necrotizing enterocolitis development,” the investigators wrote. “Further trials are needed.”

Compared with placebo, no probiotic formulation significantly improved the third primary outcome in the meta-analysis, culture-confirmed sepsis. However, several formulations were associated with moderate- or high-quality evidence for efficacy on secondary outcome measures. Compared with placebo, combinations of Lactobacillus and Bifidobacterium and Saccharomyces boulardii were associated with a significant decrease in the number of days to reach full feeding (mean reduction, 3.3 days; 95% CI, 5.9-0.7 days). Compared with placebo, single-strain therapy with B. animalis subspecies lactis or Lactobacillus reuteri was associated with a shorter duration of hospitalization, with mean reductions of 13.0 days (95% CI, 22.7-3.3 days) and 7.9 days (95% CI, 11.6-4.2 days), respectively.

“Multicenter and large randomized controlled trials should be prioritized to distinguish between the efficacy of single- and multiple-strain probiotics among preterm infants,” Dr. Morgan and her associates concluded. Such studies would further clarify the safety of probiotic formulations in this “fragile population,” they wrote. “Although the primary concern of live microbe administration, intestinal barrier translocation leading to sepsis, is decreased by several probiotic formulations, sound clinical judgement should be exercised.”

Partial support was provided by Mitacs Canada, in partnership with Nestlé Canada. The funder was not involved in designing or conducting the study or writing the manuscript. Dr. Morgan reported having no relevant conflicts of interest. One coinvestigator disclosed ties to AbbVie, Ferring, Janssen, and Takeda.

SOURCE: Morgan RL et al. Gastroenterology. 2020 Jun 24. doi: 10.1053/j.gastro.2020.05.096.

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