Defining the plasma folate concentration associated with the red blood cell folate concentration threshold for optimal neural tube defects prevention: a population-based, randomized trial of folic acid supplementation

Abstract

Background: For women of reproductive age, a population-level red blood cell (RBC) folate concentration below the threshold 906 nmol/L or 400 ng/mL indicates folate insufficiency and suboptimal neural tube defect (NTD) prevention. A corresponding population plasma/serum folate concentration threshold for optimal NTD prevention has not been established.

Objective: The aim of this study was to examine the association between plasma and RBC folate concentrations and estimated a population plasma folate insufficiency threshold (pf-IT) corresponding to the RBC folate insufficiency threshold (RBCf-IT) of 906 nmol/L.

Methods: We analyzed data on women of reproductive age (n = 1673) who participated in a population-based, randomized folic acid supplementation trial in northern China. Of these women, 565 women with anemia and/or vitamin B-12 deficiency were ineligible for folic acid intervention (nonintervention group); the other 1108 received folic acid supplementation for 6 mo (intervention group). We developed a Bayesian linear model to estimate the pf-IT corresponding to RBCf-IT by time from supplementation initiation, folic acid dosage, methyltetrahydrofolate reductase (MTHFR) genotype, body mass index (BMI), vitamin B-12 status, or anemia status.

Results: Using plasma and RBC folate concentrations of the intervention group, the estimated median pf-IT was 25.5 nmol/L (95% credible interval: 24.6, 26.4). The median pf-ITs were similar between the baseline and postsupplementation samples (25.7 compared with 25.2 nmol/L) but differed moderately (±3-4 nmol/L) by MTHFR genotype and BMI. Using the full population-based baseline sample (intervention and nonintervention), the median pf-IT was higher for women with vitamin B-12 deficiency (34.6 nmol/L) and marginal deficiency (29.8 nmol/L) compared with the sufficient group (25.6 nmol/L).

Conclusions: The relation between RBC and plasma folate concentrations was modified by BMI and genotype and substantially by low plasma vitamin B-12. This suggests that the threshold of 25.5 nmol/L for optimal NTD prevention may be appropriate in populations with similar characteristics, but it should not be used in vitamin B-12 insufficient populations. This trial was registered at clinicaltrials.gov as NCT00207558.

Keywords: Bayesian; folic acid; neural tube defects; plasma folate; red blood cell folate; vitamin B-12.

FIGURE 1

Correlation plots between plasma and RBC concentrations at baseline (month 0) and after 6 mo of supplementation. Plots show the natural log-transformed plasma and RBC folate concentrations for (A) the intervention group (baseline n = 1108, 6 mo n = 977), (B) the non-intervention group (n = 565), and different folic acid dosage groups (C: baseline n = 368, 6 mo n = 330; D: baseline n = 371, 6 mo n = 332; E: baseline n = 183, 6 mo n = 162; F: baseline n = 186, 6 mo n = 153). The values of correlation coefficients (r) are shown in each panel. RBC, red blood cell

FIGURE 2

Correlation plots between plasma and RBC concentrations at baseline (month 0) and after 6 mo of supplementation. Plots show the natural log-transformed plasma and RBC folate concentrations for MTHFR 677 genotype groups (A: baseline n = 163, 6 mo n = 159; B: baseline n = 448, 6 mo = 434; C: baseline n = 330, 6 mo n = 361) and BMI groups (D: baseline n = 670, 6 mo n = 584; E: baseline n = 287, 6 mo n = 260; F: baseline n = 69, 6 mo n = 60). Data included only women who received the folic acid intervention. The estimated correlation coefficients (r) are shown in each panel. RBC, red blood cell.

FIGURE 3

Estimated plasma folate concentration corresponding to the RBC folate concentration of 906 nmol/L using data from the intervention group (includes baseline and 6 mo). The dashed line represents the median, and the values of the estimated median and 95% credible interval are shown. CI, Bayesian credible interval; RBC, red blood cell.