­Effect of Antenatal Micronutrient Supplementation on the Plasma Proteome in School Aged Children in Nepal

Abstract

Objectives: Antenatal micronutrient interventions may influence maternal and offspring health in chronically undernourished settings; however, molecular mechanisms remain largely unexplored. We examined effects of multiple combinations of antenatal micronutrients as supplements on the plasma proteome of offspring at 6-8 years of age. Methods: We applied quantitative mass spectrometry to measure plasma protein abundance in 500 children whose mothers had been randomized to receive daily supplements of folic acid (FA), iron-folic acid (IFA), iron-folic acid-zinc (IFAZn), multiple micronutrient (MM), or placebo (control) from 1st trimester to 3 months postpartum (all tablets contained vitamin A). We identified differentially abundant proteins and sets of proteins sharing a common biological function by enrichment analysis using the Gene Ontology (GO) database. Results: With a relaxed discovery threshold (false discovery rate <0.25), maternal FA supplementation increased the abundance of insulin-like growth factor-1 (IGF1) by 33.7 (95% CI: 14.7-55.8)%; maternal IFA supplementation increased tissue inhibitor of metalloproteinase 1 by 12.5 (5.9-19.6)%.  All supplements containing iron-folic acid increased IGF1, IGF2, and IGF-binding protein 5 by 23.9 (9.1-40.7)%, 28.6 (10.7-49.4)%, and 23.7 (10.5-38.5)%, respectively, and decreased stromal interaction molecule 1 by 63.3 (36.7-78.8)%. With a discovery threshold of 0.05, maternal IFA supplementation negatively enriched proteins localized in microtubules (GO:5874) with an enrichment score (ES) of -0.62 and maternal IFA and MM supplementation positively enriched proteins with growth factor activity (GO:8083) with ES of 0.70 and 0.75, respectively (all p-values <0.0001). Conclusions: Antenatal micronutrient supplementation exerts subtle metabolic effects on proteins involved in regulating growth/development and intracellular structure in school-aged children.