Maternal betaine and methylation potential during pregnancy are associated with child growth at birth and early childhood: results of the CHiMINCs-II cohort study

BACKGROUND: One-carbon metabolism regulates growth through methyl group transfer required for DNA synthesis and epigenetic processes. In folate-replete populations, the contribution of betaine-dependent remethylation and methylation potential to postnatal growth remains unclear. OBJECTIVE: Examine if maternal plasma concentrations of betaine, methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), cystathionine, and the SAM:SAH ratio are associated with offspring growth and body composition at birth and during early childhood. METHODS: This study included 150 mother-child dyads randomly selected from the prospective CHiMINCs-II cohort. Maternal fasting plasma concentrations of betaine, methionine, SAM, SAH, and cystathionine were quantified by LC-MS/MS before 30 weeks of gestation. Anthropometric outcomes at birth (weight, length, head circumference) and at two to three years of age (weight, height, BMI-for-age, weight-for-height), as well as body composition (fat mass and fat-free mass), were assessed in children. Associations were evaluated using multivariable linear regression models adjusted for pre-pregnancy BMI, child sex, gestational age at birth, and gestational age at blood collection. RESULTS: Maternal betaine concentrations showed no significant associations with anthropometric measures at birth. In contrast, higher maternal betaine concentrations were associated with greater child weight, weight-for-height z-score, and BMI-for-age z-score at two to three years. Higher SAM:SAH ratio was associated with lower child weight and weight gain, whereas SAM and SAH concentrations showed opposing associations consistent with their roles in methylation balance. Methionine concentrations were positively associated with multiple growth outcomes. Betaine and methionine concentrations were positively associated with fat mass, while SAM concentrations were inversely associated with fat-free mass at two to three years. CONCLUSIONS: Maternal plasma concentrations of betaine and methylation potential during pregnancy are differentially associated with early childhood growth and body composition in a folate-replete population. These findings support a role for maternal one-carbon metabolism in shaping postnatal growth trajectories, beyond the neonatal period.