Limited Evidence of Benefits from Clinical Trials of Human-Identical Milk Oligosaccharides for Infants

Human milk oligosaccharides (HMOs) are complex carbohydrates unique to human milk, and a wealth of observational and mechanistic studies indicate that HMOs are key to infant health by supporting gut microbiota and immune development. This review synthesizes evidence from randomized clinical trials evaluating whether supplementation with human-identical milk oligosaccharides (HiMOs), i.e., synthetic HMOs, in infants and young children improves health outcomes. We identified 12 randomized clinical trials: 8 in healthy infants, 3 in special populations of infants, and 1 in young children. We selected only trials with a randomized, parallel group design; most of the included trials also had an observational human milk-fed control group. The most widely evaluated HiMO was 2'-fucosyllactose used alone or in combination with other HiMOs. In some trials, other bioactive components were included in the control and/or intervention formula groups, complicating interpretation. All trials in healthy infants confirmed the noninferiority of HiMO-supplemented formula on growth and tolerability relative to control formula. Results were mixed with respect to reductions in morbidity, and all studies were underpowered for more severe morbidity outcomes. Stool microbiota and biomarkers of inflammation and gut function generally shifted in a direction closer to human milk-fed infants with HiMO intervention. Some growth improvements were noted in association with HiMO intervention in preterm infants and in infants with severe acute malnutrition. HiMO supplementation may be a promising intervention to improve child health, but due to the heterogeneity and limitations of the clinical trials that have been undertaken, many questions remain about the nature of the benefits and the specific populations who might benefit.