Dependence of bioavailability of folic acid and (6S)-5-methyltetrahydrofolate on baseline red blood cell folate concentrations in infants

Background: Folate bioavailability may depend on folate status of an individual and the form of folate presents in foods. Objective: We studied whether changes of red blood cell (RBC)-folate concentrations following dietary intervention with folic acid or the calcium salt of (6S)-5-methyltetrahydrofolate (5-MTHF-Ca) depend on baseline RBC-folate and differ by the folate form provided. Methods: We studied 167 infants randomized to infant formula with either 15.2 μg folic acid or 15.8 μg 5-MTHF-Ca per 100 kcal from <1 month of age (baseline visit) until age 16 weeks (visit 4). Generalised Additive Models (GAMs) were used to study whether the changes in RBC-folate concentrations between baseline visit and visit 4 (study outcome) depend on the intervention (folic acid or 5-MTHF-Ca), length of the intervention and a smooth effect of baseline RBC-folate concentrations for each intervention group. Results: The GAM base model showed that the change of RBC-folate was higher in infants with lower baseline RBC-folate concentrations. This model explained 42 % of the deviance in the data. For the group that received folic acid, this effect was estimated to be linear (effective degrees of freedom = 1). In the group receiving 5-MTHF-Ca, the effect of baseline RBC-folate on the change of RBC-folate was non-linear. The smooth effect of baseline RBC-folate on the change of RBC-folate concentrations differed between the intervention groups (p = 0.002). In infants with higher baseline RBC-folate concentrations, the change of RBC-folate concentration is systematically higher in the 5-MTHF-Ca group than in the folic acid group. Conclusion: The bioavailability of folic acid and 5-MTHF-Ca shows physiological decline when baseline RBC-folate is high. The reduction of the bioavailability is more pronounced after folic acid intake. The results may impact infant's intake recommendations from different folate forms. The molecular mechanisms behind these results deserve further investigations.