Sex differences in the associations of human milk oligosaccharides with height and weight in breastfed Ugandan children

Background & Objective Human milk oligosaccharides ( HMOs) have been associated with several child growth metrics, but there was no difference in the associations according to child sex. Here, we present clinic-based cross-sectional data on the relationship between specific HMOs in the milk of Ugandan mothers and growth in their breastfed children as a group and as males and females separately. Method Human milk samples were manually collected from 127 lactating mothers. Levels of human milk oligosaccharides (HMOs) were analyzed by high-performance liquid chromatography (HPLC). Children’s weight and length were measured using a portable digital scale and length board, respectively. Weight-for-age (WAZ), height-for-age (HAZ) and weight for height (WHZ) Z scores were calculated. The relationships between HMOs and untransformed weights and heights and between WAZ, HAZ and WHZ subcategories were analyzed for all children and for males and females separately by Spearman’s correlation and Kruskal‒Wallis and Mann‒Whitney U tests. Results There were positive and negative correlations between the concentrations of specific HMOs and the heights and weights of children according to mothers’ secretor status. Tall infant stature was associated with higher concentrations of 6’SL, LSTc, DFLNH, DSLNH, LNnT and total HMOs in secretor or nonsecretor mothers; short infant stature was associated with higher concentrations of 3FL and DFLac; overweight was associated with higher concentrations of 6’SL, LSTc and LNnT in secretor and nonsecretor mothers; and normal weight was associated with higher concentrations of 3’FL. The associations between maternal HMO levels and childrens heights and weights or between the LAZ, WAZ and WHZ subcategories significantly differed between male and female children. Conclusions There are sex differences in the associations between high concentrations of some HMOs and stature and weight in Ugandan children born to secretor and nonsecretor mothers. Highlights Plain Language Summary Human milk oligosaccharides ( HMOs) have been associated with growth parameters of children in the Americas, Europe and Asia. Only two such studies have been conducted in Africa. None of the studies investigated the relationship between child sex and HMO composition and growth interactions. We examined the relationship between 19 well-characterized HMOs and growth metrics and also dissected the data by infant sex. Our results show a positive correlation between some HMOs and growth indices in either female or male children only. This highlights the impact of sex differences in the relationship between specific HMOs and growth measures in children. This evidence, if validated, could inform future nutritional interventions involving combinations of HMOs as food supplements that are equally effective for both male and female children. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Thomas Egwang received funding from the Global Innovation Fund, and Grand Challenges Canada. The funders played no role in the study design, data collection and analysis, preparation of the manuscript or decision to publish this paper. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Uganda National Council for Science and Technology and the Research Ethics Committee of the Vector Division, Ministry of Health, approved the original HD4MC study. All mothers who donated milk samples and brought infants to the study clinic for weight and height measurements and health assessment signed or thumb-printed an informed consent form. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets supporting the conclusion of this article will be made available upon request from TGE.