Multistrain probiotics improve survival outcomes in preemies

Multistrain probiotics confer significant mortality-reduction benefit in preterm infants, according to the results of a network meta-analysis.

Pooled data from 106 trials involving 25,840 preterm infants showed that multiple-strain probiotics lowered all-cause mortality by 31 percent compared with placebo (risk ratio [RR], 0.69, 95 percent confidence interval [CI], 0.56–0.86; risk difference [RD], −1.7 percent, 95 percent CI, −2.4 to −0.8). [JAMA Pediatr 2023;doi:10.1001/jamapediatrics.2023.3849]

Significant beneficial effects were also seen for other outcomes. Notably, multiple-strain or single-strain probiotics combined with prebiotics or lactoferrin were associated with the greatest reduction in severe necrotizing enterocolitis (RR, 0.13, 95 percent CI, 0.05–0.37; RD, −5.1 percent, 95 percent CI, −5.6 to −3.7), sepsis (RR, 0.33, 95 percent CI, 0.14–0.78; RD, −10.7 percent, 95 percent CI, −13.7 to −3.5), feeding intolerance (RR, 0.45, 95 percent CI, 0.29–0.67; RD, −14.1 percent, 95 percent CI, −18.3 to −8.5), and the time to reach full enteral feeding (mean difference [MD], −2.03 days, 95 percent CI, −3.04 to −1.02).

Only single-strain and multiple-strain probiotics outperformed placebo at reducing duration of hospitalization (MD, −3.31 days, 95 percent CI, −5.05 to −1.58 and MD, −2.20 days, 95 percent CI, −4.08 to −0.31, respectively).

“We did not observe any effect modification for risk of bias, birth weight, gestational age, feeding with breast milk, or delivery type,” the investigators said.

These findings are consistent with those of two previously published network meta-analyses showing that a combination of probiotics strains is usually better than any single-strain probiotics. However, there is not enough studies addressing particular strains or combinations of strains regarding comparative benefits. [Gastroenterology 2020;159:467-480; J Pediatr Gastroenterol Nutr 2018;67:103-122]

Combined effects

“The enhanced preventive effects of multiple-strain probiotics compared with single-stain formulations might be owing to the combined effects of multiple strains, each with specific biological properties (eg, anti-inflammatory, immune modulation, intestinal motility, epithelial barrier function) or simply the consequence of a higher probiotic dose,” the investigators explained. [PLoS One 2017;12:e0171579]

Meanwhile, the mechanisms of action underlying the beneficial effects of synbiotics and combination products remain unclear but might be based on an additive or synergistic interaction when combining lactoferrin or prebiotics and probiotics, the investigators said. [Adv Nutr 2016;7:928-937]

“One possible explanation is that prebiotics and lactoferrin can act as a food source for probiotic colonization. In healthy term infants, the capacity of bifidobacteria strains to consume human milk oligosaccharides present in human breast milk as substrate is considered a primary mechanism promoting bacterial colonization,” they added. [Semin Perinatol 2017;41:41-51; Glycobiology 2013;23:1281-1292]

Moderate- to high-certainty evidence

Overall, the network meta-analysis provides moderate- to high-certainty evidence that multiple-strain probiotics are associated with reduced mortality and are among the best interventions associated with important reductions in all-cause mortality, severe necrotizing enterocolitis, late-onset sepsis, feeding intolerance, time to reach full feeding, and duration of hospital stay.

“The most severe harm associated with the use of probiotics for prevention of morbidity and mortality in preterm infants is sepsis caused by administered probiotics due to translocation across the intestinal epithelial barrier. This is reported to be extremely rare with none of our included studies reporting cases of probiotic-associated sepsis, which is consistent with what other recent systematic reviews have reported,” the investigators said. [Semin Perinatol 2017;41:41-51; Clin Infect Dis 2015;60:S129-S134; PLoS One 2017;12:e0171579]

Of the trials included in the network meta-analysis, 41 and 44 assessed single-strain and multiple-strain probiotics, respectively, 13 evaluated combination products, 10 examined lactoferrin, and six looked at oligosaccharides (human milk oligosaccharides, fructo-oligosaccharides, and/or galacto-oligosaccharides). A total of 16 different probiotic strains were used across the studies that evaluated multiple-strain probiotics and combination products, most of which included both Bifidobacterium and Lactobacillus species.

The median of the mean birth weight was 1,237.1 g, and the median of the mean gestational age was 30.0 weeks.

As for evidence quality, 72 trials had a low risk of bias in terms of allocation concealment and 88 in terms of missing participant outcome data. Twenty-five studies had a high risk of bias for blinding of infants’ parents/caregivers and study personnel, while 48 studies had a high risk of bias for masking of outcome assessments.