Determining an optimal plasma folate concentration associated with the prevention of neural tube defects
Authors: Sekkarie Ahlia , Berry RJ , Qi Yan Ping , Crider Krista 
Published: November 2023

The World Health Organization (WHO) recently released guidelines that recommend red blood cell (RBC) folate concentrations above 400 ng/ml(906 nmol/L) (using the microbiologic assay) for optimal protection from having a neural tube defect‐affected pregnancy. This threshold RBC folate concentration should be used to evaluate such risk among different populations of childbearing age women. However, many population‐based surveys do not measure RBC folate concentrations, relying instead on plasma or serum folate concentrations, which do not yet have avalidated threshold associated with optimal protection against neural tube defects. We sought to establish such a threshold by estimating the correlation between plasma folate concentrations and the optimal RBC folate concentration as recommended by WHO guidelines. We used paired RBC folate and plasma folate concentrations that were collected from a randomized control trial in China of folic acid supplementation (N=1108 women of child bearing age).We found that at baseline there was significant correlation between RBC and plasma folate concentrations (Pearson correlation 0.425 two tail P < 0.0001). After six months of folic acid supplementation at 100, 400 or 4,000 μg/day there remained significant correlations at all dosages (Pearson correlations between 0.153–0.566).However, when the data were limited to women with RBC folate concentrations above the optimal threshold (range 906–1300nmol/L) the associated mean plasma folate concentrations varied widely by dose and duration of folic acid supplementation. At baseline (no folic acid intake in the previous three months), optimal RBC folate concentration was associated with a mean plasma folate concentration of 17 nmol/L. However, after months of folic acid supplementation, women with RBC folate concentrations in the optimal range had very different mean plasma folate concentrations. After 3 months supplementation with 100 μg/day, 400μg/day, or 4,000 μg/day, women with RBC folates in the optimal range had mean plasma folate concentrations = 32 nmol/L, 49 nmol/L, and 113 nmol/L, respectively; after 6 months supplementation with 100 μg/day, 400 μg/day, or 4,000 μg/day, mean plasma folate concentrations = 40 nmol/L, 41 nmol/L, and 71 nmol/L, respectively).Among women who have achieved optimal blood folate concentrations, associated plasma folate concentrations vary up to six fold depending on folic acid intake (yes/no), folic acid dose and duration of supplementation. If these results are consistent with those from other studies, establishing a single threshold for plasma folate concentrations seems unlikely as plasma folate concentrations increase more rapidly with folic acid supplementation than do RBC folate concentrations and the magnitude of that increase is dependent on the dosage and duration of folic acid supplementation.Support or Funding InformationAhlia Sekkarie supported in part by an appointment to the Research Participation Program at the CDC administered by ORISE.