Use of a Liquid Supplement Containing 2 Human Milk Oligosaccharides: The First Double-Blind, Randomized, Controlled Trial in Pre-term Infants

Abstract

There is growing evidence supporting the benefit of human milk oligosaccharides (HMOs) on reducing risk of illnesses and improving immune function in newborn infants, but evidence in pre-term infants is lacking. This randomized, double-blind, placebo-controlled trial (NCT03607942) of pre-term infants evaluated the effects of HMO supplementation on feeding tolerance, growth, and safety in 7 neonatal units in France. Pre-term infants (27–33 weeks' gestation, birth weight <1,700 g) were randomized early after birth to receive HMO supplement (n = 43) [2′-fucosyllactose (2′FL) and lacto-N-neotetraose (LNnT) in a 10:1 ratio (0.374 g/kg body weight/day)] or an isocaloric placebo (n = 43) consisting of only glucose (0.140 g/kg/day) until discharge from the neonatal unit. Anthropometric z-scores were calculated using Fenton growth standards. Primary outcome was feeding tolerance, measured by non-inferiority (NI) in days to reach full enteral feeding (FEF) from birth in HMO vs. placebo group (NI margin = 4+ days). Mean number of days on intervention prior to FEF was 8.9 and 10.3 days in HMO and placebo, respectively. Non-inferiority in time to reach FEF in HMO (vs. placebo) was achieved [LS mean difference (95% CI) = −2.16 (−5.33, 1.00); upper bound of 95% CI < NI margin] in full analysis set and similar for per protocol. Adjusted mean time to reach FEF from birth was 2 days shorter in HMO (12.2) vs. placebo (14.3), although not statistically significant (p = 0.177). There was no difference in weight-for-age z-scores between groups throughout the FEF period until discharge. Length-for-age z-scores were higher in HMO at FEF day 14 [0.29 (0.02, 0.56), p = 0.037] and 21 [0.31 (0.02, 0.61), p = 0.037]. Head circumference-for-age z-score was higher in HMO vs. placebo at discharge [0.42 (0.12, 0.71), p = 0.007]. Occurrence of adverse events (AEs) was similar in both groups and relatively common in this population, whereas 2.3 and 14.3%, respectively, experienced investigator-confirmed, related AEs. HMO supplementation is safe and well-tolerated in pre-term infants. After 9 days of supplementation, the HMO group reached FEF 2 days earlier vs. placebo, although the difference was not statistically significant. In addition, HMO supplementation supports early postnatal growth, which may have a positive impact on long-term growth and developmental outcomes.

Prebiotics in the management of pediatric gastrointestinal disorders: Position paper of the ESPGHAN special interest group on gut microbiota and modifications

“…The authors reported no differences in morbidity or mortality, except for a nonsignificant trend in reducing time to full enteral feeding (12.2 days in HMLOs group vs. 14.4 days in placebo group). In addition, head circumferences of infants who had received the HMLOs were significantly larger than those in the control group, although a clear hypothesis for this finding is lacking 7 …”

“…In addition, head circumferences of infants who had received the HMLOs were significantly larger than those in the control group, although a clear hypothesis for this finding is lacking. 7 In summary, the number of included studies investigating the use of prebiotic supplements in preterm infants is low. None of the studies showed clear benefits on outcomes.…”

“…36 In the pilot RCT conducted by Riskin et al, 17 with a total of 28 participants, no clear benefits were observed from the administration of lactulose to infants. Only one additional RCT was identified by databases searches following the publication of the meta-analysis by Chi et al 6,7 In this trial, a total of 86 preterm newborns, born between 27 and 33 weeks' gestation, were randomly assigned to receive either a placebo or a mixture of two human milk-like oligosaccharides (HMLOs), specifically 2′ FL and lacto-N-neotetraose (LNnT) during their hospitalization. The authors reported no differences in morbidity or mortality, except for a nonsignificant trend in reducing time to full enteral feeding (12.2 days in HMLOs group vs. 14.4 days in placebo group).…”

Clinical Studies on the Supplementation of Manufactured Human Milk Oligosaccharides: A Systematic Review

“…Other studies assessed 2′-FL and LNnT in infants diagnosed with cows’ milk protein allergy (CMPA) for 1 week [ 55 ] or for 4 months plus a voluntary follow-up until 12 months of age [ 57 , 58 ]. In preterm infants, 2′-FL and LNnT mixtures were supplemented at a ratio of 10:1 (0.374 g/kg body weight/d) [ 59 ]. A mix of five HMOs (2′-FL, 3-FL, LNT, 3′-SL, and 6′-SL) with a total concentration of 5.75 g/L was tested in two infant studies for 4 months, with a voluntary follow-up at 6 months [ 49 , 52 ].…”

The role of Klebsiella populations in preterm infants

“…The differential exposure of preterm and full-term infants to antibiotic therapy, microbiological and environmental components, immune status and hospital stay influence neonatal microbiome development in these infant groups [ 55 ]. Several recent studies have investigated the gut microbiota of preterm infants, in some cases focusing on specific neonatal clinical outcomes ( Supplementary Table S1 ) and in other cases considering diet [synbiotics, prebiotics, probiotics or different milks (breast milk, fortified breast milk, formula milks)] or therapeutic regimes targeting improved clinical outcomes [ 56–61 ].…”