Safety and tolerance of infant formulas containing probiotics: a multicenter, randomised, controlled trial in healthy term infants

Several studies have documented the safety and tolerance of probiotics in infants, however, most studies have been conducted with supplements. This randomised, double-blind, multicenter trial evaluated growth of healthy term infants fed infant formula supplemented with Limosilactobacillus reuteri DSM17938 (L. reuteri; n = 92) or Bifidobacterium lactis CNCM I-3446 (B. lactis; n = 92) or the same formula without probiotics ( n = 95). Mixed feeding with breast milk was allowed in each group. Exclusively breastfed infants ( n = 100) were included for reference. Non-inferiority in weight gain (margin -3 g/day) from enrolment to age 6 months was the primary outcome. Length, BMI, head circumference, and WHO z-scores from birth to 12 months were assessed, as was digestive tolerance, and, in a subset of infants, urinary D-lactate parameters and abundance of key bacteria in fecal matter. Of 279 infants randomised, 256 completed the study. The mean difference in weight gain between each probiotic group and the standard group at age 6 months was -0.378 g/day (97.5% confidence interval (CI), -1.541, 0.776; P < 0.001) for L. reuteri and -1.724 g/day (97.5% CI, -2.845, -0.603; P = 0.005) for B. lactis, indicating non-inferior growth. Anthropometric z-scores were not significantly different between any of the formulas, over the entire study, except for a slightly lower weight-for-age z-score in the B. lactis vs standard group at 8 months ( P = 0.034). No differences in adverse events or urinary D-lactate levels were observed. Significantly higher fecal lactobacilli counts were observed with L. reuteri supplementation ( 7.0 log 10 (CFU/g); n = 24) compared with standard formula ( 6.2 log 10 (CFU/g); n = 21). Parent-reported digestive tolerance symptoms were similar between the formula groups and comparable to the breastfed group. Weight gain from enrolment to age 6 months in infants fed formula containing probiotics L. reuteri DSM17938 or B. lactis CNCM I-3446 was non-inferior versus infants fed the same formula without probiotics. Both probiotic formulas were safe and well-tolerated.