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Randomized Controlled Trial
. 2018 Aug;57(5):1771-1780.
doi: 10.1007/s00394-017-1461-8. Epub 2017 Apr 26.

The Effectiveness of Daily Supplementation With 400 or 800 µg/Day Folate in Reaching Protective Red Blood Folate Concentrations in Non-Pregnant Women: A Randomized Trial

Free PMC article
Randomized Controlled Trial

The Effectiveness of Daily Supplementation With 400 or 800 µg/Day Folate in Reaching Protective Red Blood Folate Concentrations in Non-Pregnant Women: A Randomized Trial

Rima Obeid et al. Eur J Nutr. .
Free PMC article


Purpose: Folate required to achieve desirable red blood cell (RBC) folate concentrations within 4-8 weeks pre-pregnancy is not known. We studied the effect of supplementation with 400 or 800 µg/day folate in achieving RBC-folate ≥906 nmol/L.

Methods: Non-pregnant women were randomized to receive multinutrient supplements containing 400 µg/day (n = 100) or 800 µg/day (n = 101) folate [folic acid and (6S)-5-CH3-H4folate-Ca (1:1)]. The changes of folate biomarkers were studied after 4 and 8 weeks in the 198 women who returned at least for visit 2.

Results: At baseline, 12 of the 198 participants (6.1%) had RBC-folate <340 nmol/L, but 88% had levels <906 nmol/L. The RBC-folate concentrations increased significantly in the 800 µg/day (mean ± SD = 652 ± 295 at baseline; 928 ± 330 at 4 weeks; and 1218 ± 435 nmol/L at 8 weeks) compared with the 400 µg/day [632 ± 285 at baseline (p = 0.578); 805 ± 363 at 4 weeks (p < 0.001); 1021 ± 414 nmol/L at 8 weeks (p < 0.001)]. The changes of RBC-folate were greater in the 800 µg/day than in the 400 µg/day at any time (changes after 8 weeks: 566 ± 260 vs. 389 ± 229 nmol/L; p < 0.001). Significantly more women in the 800 µg group achieved desirable RBC-folate concentrations at 4 weeks (45.5 vs. 31.3%; p = 0.041) or 8 weeks (83.8 vs. 54.5%; p < 0.001) compared with the 400 µg group. RBC-folate levels below the population median (590 nmol/L) were associated with a reduced response to supplements.

Conclusions: 88% of the women had insufficient RBC-folate to prevent birth defects, while 6.1% had deficiency. Women with low RBC-folate were unlikely to achieve desirable levels within 4-8 weeks, unless they receive 800 µg/day. The current supplementation recommendations are not sufficient in countries not applying fortification.

Trials register: The trial was registered at The German Clinical Trials Register: DRKS-ID: DRKS00009770.

Keywords: (6S)-5-CH3-H4folate-Ca; Folic acid; Homocysteine; Neural tube defects; Preconceptional; RBC-folate; Supplementation.

Conflict of interest statement

The authors have no conflict of interest regarding the content of this manuscript. All authors have read and approved the final article. BioTeSys GmbH is an independent third party research institute that was responsible for designing the study, recruitment, performance, data collection, measurements and data analyses. BioTeSys GmbH kept record of the original data and is responsible for the data integrity and final analyses. The study was initiated and sponsored by Merck Selbstmedikation GmbH. The sponsor contributed to discussions about study design and selection of outcome measures prior to the start of the study, but it had no role in conducting the study, data analysis, and reporting the results.


Fig. 1
Fig. 1
Mean concentrations of RBC-folate at baseline, 4 and 8 weeks after supplementation with 400 and 800 µg/day folate according to baseline RBC-folate (<, ≥group median 590 nmol/L). The percentages within the column indicate the % of women reaching RBC-folate levels ≥906 nmol/L in the subgroups

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