The Journal of Nutrition · 7 authors, 5 centres
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Supplementing young children (6–30 months) with both vitamin B12 and folic acid for 6 months led to lower homocysteine levels 6–7 years later, a marker of cardiovascular risk. The effect was most notable in children who were underweight or stunted, suggesting early B-vitamin supplementation may have lasting metabolic benefits. These findings support targeted micronutrient interventions in malnourished populations to potentially reduce future cardiovascular disease risk.
**Background:** Cardiovascular diseases (CVDs) account for 32% of global deaths, with over three-quarters occurring in low- and middle-income countries (LMICs). Although clinical CVD manifests in adulthood, its pathogenesis begins in early life, making early intervention crucial. Deficiencies of vitamin B12 and folate are common in LMICs and are associated with elevated homocysteine (tHcy), a known cardiometabolic risk marker. These vitamins are essential cofactors for converting homocysteine to methionine. Observational studies have linked high tHcy to premature CVD risk in children and adolescents, but randomized trials in adults have not shown CVD benefit from homocysteine-lowering interventions. Additionally, leptin and adiponectin are adipokines associated with cardiometabolic risk; animal studies suggest B-vitamin supplementation may favorably alter their levels, but human data are lacking. This study aimed to evaluate the long-term effect of vitamin B12 and/or folic acid supplementation in early childhood on cardiometabolic risk markers after 6–7 years.
**Methods:** This is a follow-up of a 2×2 factorial, double-blind, randomized controlled trial conducted in urban neighborhoods of Tigri and Dakshinpuri, New Delhi, India. Originally, 1000 children aged 6–30 months were enrolled from January 2010 to September 2011. They were randomized in a 1:1:1:1 ratio to receive daily for 6 months: vitamin B12 (1.8 μg), folic acid (150 μg), both, or placebo, provided as a lipid-based supplement. Approximately 6 years later (September 2016–November 2017), families were contacted for follow-up. Of the original 1000, 10 died, 52 refused consent, and 145 moved away, leaving 791 children re-enrolled. Blood samples were collected for measurement of tHcy (n=776), and in a randomly selected subsample of 274 children, leptin, total adiponectin, and high molecular weight (HMW) adiponectin were measured. tHcy was analyzed using commercial kits (Abbott Laboratories), and leptin and adiponectin by ELISA (Alpco). Statistical analysis used generalized linear models with Gaussian family and identity link, adjusting for baseline BMI. Subgroup analyses were prespecified for stunting, wasting, and underweight at baseline.
**Key Results:** At baseline, 32% of children had vitamin B12 deficiency (<200 pmol/L) or folate deficiency (<7.5 nmol/L). The mean age at follow-up was 7.4 years (SD 0.7). Compared to placebo, combined supplementation with vitamin B12 and folic acid resulted in a significantly lower tHcy concentration after 6–7 years: adjusted mean difference −1.19 μmol/L (95% CI: −2.30, −0.09; p<0.05). No significant differences were observed for leptin, total adiponectin, or HMW adiponectin in the overall analysis. In subgroup analyses, vitamin B12 supplementation reduced leptin concentration and the leptin/total adiponectin ratio (LAR) and leptin/HMW adiponectin ratio (LHMWR) in stunted children. Folic acid supplementation decreased LAR and LHMWR in wasted children. No significant effects were seen for homocysteine in subgroups.
**Clinical Implications:** This study provides evidence that early-life supplementation with vitamin B12 and folic acid can have persistent beneficial effects on homocysteine levels, a key cardiometabolic risk marker, for at least 6–7 years. The reduction of 1.19 μmol/L in tHcy, while modest, may be clinically significant given that in adults a 3 μmol/L reduction is associated with a 16% lower risk of ischemic heart disease. The beneficial effects on leptin and adiponectin ratios in malnourished subgroups suggest that targeted supplementation in undernourished children could improve insulin sensitivity and reduce future cardiometabolic risk. These findings support the importance of ensuring adequate B-vitamin intake in early childhood, especially in populations with high rates of deficiency. However, the study's limitations include the small subsample for adipokine measurements (n=274) and the potential for type I errors due to multiple comparisons. Further research with larger sample sizes and longer follow-up into adulthood is needed to confirm whether these biomarker changes translate into reduced CVD incidence.