Human Breast Milk 3’-Sialyllactose Positively Associates with Language Development During Infancy

Background: Genetic polymorphisms leading to variations in human milk oligosaccharide (HMO) composition have been reported. Alpha-Tetrasaccharide (A-tetra), an HMO, has been shown to only be present (>limit of detection; A-tetra+) in the human milk (HM) of women with blood type A, suggesting genetic origins determining the presence or absence (A-tetra-) of A-tetra in HM. Objectives: This study aimed to determine whether associations exist between HMO concentrations and cognitive development, and whether the associations vary between A-tetra+ and A-tetra- groups in children (<25 months old). Methods: We enrolled typically developing children (2–25 months old; mean, 10 months old) who were at least partially breastfed at the study visit. The Mullen Scales of Early Learning (MSEL) were used as the primary outcome measure to assess early cognitive development. Linear mixed effects models were employed by stratifying children based on A-tetra levels (A-tetra+ or A-tetra- ) to assess associations between age-removed HMO concentrations and both MSEL composite scores and the 5 subdomain scores. Results: A total of 99 mother-child dyads and 183HMsamples were included (A-tetra+: 57 samples, 33 dyads; A-tetra-: 126 samples, 66 dyads). No significant association was observed between HMOs and MSEL when all samples were analyzed together. The composite score and 3’-sialyllactose (3’-SL) levels were positively associated [P = 0.002; effect size (EF), 13.12; 95% CI, 5.36–20.80] in the Atetra + group. This association was driven by the receptive (adjusted P = 0.015; EF, 9.95; 95% CI, 3.91–15.99) and expressive (adjusted P = 0.048; EF, 7.53; 95% CI, 2.51–13.79) language subdomain scores. Furthermore, there was an interaction between 3’-SL and age for receptive language (adjusted P = 0.03; EF, -14.93; 95% CI, - 25.29 to -4.24). Conclusions: Our study reports the association of 3’-SL and cognition, particularly language functions, in typically developing children who received HM containing detectable A-tetra during infancy.