Red cell folate
Red cell folate reflects folate status over the roughly 120-day life of red cells. WHO puts deficiency below 100 ng/mL by anemia risk and below 151 by homocysteine, and sets 400 as a population threshold for women of reproductive age. Higher levels in early pregnancy were linked to fewer neural tube defects. Results differ by assay.
- Status
- A blood test ordered by a clinician. FDA classifies folic acid test systems, used in the diagnosis and treatment of megaloblastic anemia, as class II devices, in a regulation that describes them as measuring folic acid in plasma and serum [1].
- Measures
- The concentration of folate inside red blood cells, which take up folate only while they are being formed and live about 120 days, so WHO describes it as an indicator of long-term folate status [2].
- Also called
- RBC folate, red blood cell folate, erythrocyte folate, folate RBC, folate red cell, RBC folic acid, red cell folic acid
- Tested for
- folate deficiency, long-term folate status, anemia workup, planning a pregnancy, poor diet, heavy alcohol use, checking a folic acid supplement
Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on
Linked in research2
- ModerateLinked to fewer neural tube defects at higher levels in early pregnancy, an estimated 25 per 10,000 births at about 221 ng/mL and 6 at about 521.
- LimitedLimited evidence: two US survey analyses linked the highest red cell folate levels to more cardiovascular deaths in adults with hypertension.
Reported risks0
No risks sourced yet.
Reference ranges
Each range is the one its source published, in ng/mL. Also reported in nmol/L. Where sources differ, each is shown.
World Health Organization, 1968 threshold restated in 2015, macrocytic anemia as the indicator
All age groups · [2]
| Range | What the source calls it |
|---|---|
| below 100 ng/mL | "deficiency" |
| 100 or above ng/mL | No name given |
The value indicative of deficiency was based on the concentrations at which macrocytic anemia is more likely to appear, measured by a microbiological assay. WHO prints it as below 100 ng/mL (below 226.5 nmol/L) and gives the conversion used on this page, 1 ng/mL = 2.265 nmol/L. The same table sets serum folate deficiency at below 3 ng/mL, which is a different test with its own scale, so a red cell result cannot be placed against it. WHO gives no band above the cut-off for red cells [2].
World Health Organization, 2005 consultation restated in 2015, homocysteine as the indicator
All age groups · [2]
| Range | What the source calls it |
|---|---|
| below 151 ng/mL | "folate deficiency" |
| 151 or above ng/mL | No name given |
The cut-off is the folate concentration below which homocysteine starts to rise, taken from US survey data on men and women aged 30 and older. WHO prints it as below 151 ng/mL (below 340 nmol/L), measured by radioimmunoassay, and notes that those measurements need adjustment to be comparable with the microbiological assay. It states that the values may not be appropriate in pregnancy, when folate concentrations typically decline, and are not adequate thresholds for preventing neural tube defects [2].
World Health Organization, 2015, women of reproductive age at the population level
Women of reproductive age, as a threshold for populations and not for an individual woman · [2]
| Range | What the source calls it |
|---|---|
| below 400 ng/mL | "folate insufficiency" |
| above 400 ng/mL | "folate sufficiency" |
WHO sets above 400 ng/mL (906 nmol/L) as the red cell folate level for this group, at the population level, that achieves the greatest reduction of neural tube defects. Its table states that the thresholds are not for use at an individual level to determine the risk of an affected pregnancy, since low folate is not responsible for all neural tube defects. The table prints above 400 and below 400 and assigns no band to exactly 400. WHO notes that different calibrators or microorganisms in the microbiological assay may necessitate an adjustment of the threshold [2].
Institute of Medicine, Dietary Reference Intakes, 1998
Adults, as the cut-off used to set US dietary reference intakes for folate · [3]
| Range | What the source calls it |
|---|---|
| below 140 ng/mL | No name given |
| 140 or above ng/mL | "adequate folate status" |
The report chose 305 nmol/L (140 ng/mL) of erythrocyte folate as the cut-off point for adequate folate status. It drew on an experiment in which an early blood sign of deficiency appeared at about the time red cell folate fell under that value, and on 40 patients with megaloblastic anemia from folate deficiency, all of whom had values under it [3]. A later analysis by US survey scientists describes this cut-off as derived with a microbiological assay and reports that applying it to results from a different assay misstates how many people fall below it [4].
US Centers for Disease Control and Prevention risk categories, Tinker and colleagues, 2015
Women of childbearing age who are not pregnant, as categories of neural tube defect risk for a population with that red cell folate level · [5]
| Range | What the source calls it |
|---|---|
| 308.6 or below ng/mL | "High" |
| 309.1 to 399.6 ng/mL | "Elevated" |
| 400 to 661.8 ng/mL | "Optimal" |
| 662.3 or above ng/mL | "Limited additional benefit" |
The paper prints the categories in nmol/L for the assay used in the Irish and Chinese studies they were derived from: 699 or below, 700 to 905, 906 to 1,499 and 1,500 or above. They are converted here and rounded to one decimal. The categories correspond to an estimated more than 14, 9 to 14, and 4 to under 9 neural tube defects per 10,000 live births, with the top category outside the range that could be estimated. For the assay used in the US national survey the same categories are 585 or below, 586 to 747, 748 to 1,215 and 1,216 or above nmol/L, so the numbers depend on the assay. By the survey's assay, 22.8% of US women aged 12 to 49 who were not pregnant were below the Optimal category in 2007 to 2012 [5].
Swiss SENIORLAB study reference interval, Risch and colleagues, 2015, men
Men aged 60 and older · [6]
| Range | What the source calls it |
|---|---|
| below 199.6 ng/mL | No name given |
| 199.6 to 832.2 ng/mL | "reference interval" |
| above 832.2 ng/mL | No name given |
The 2.5th to 97.5th percentiles in Swiss adults aged 60 and older whom the authors describe as "subjectively healthy", printed as 452 to 1,885 nmol/L and converted here. Red cell folate was estimated from a whole blood measurement on one immunoassay analyzer together with the hematocrit. Red cell folate did not change with age in this group, while serum folate fell [6]. The lower limit sits above both WHO deficiency cut-offs, which were set on other assays [2].
Swiss SENIORLAB study reference interval, Risch and colleagues, 2015, women
Women aged 60 and older · [6]
| Range | What the source calls it |
|---|---|
| below 192.1 ng/mL | No name given |
| 192.1 to 912.6 ng/mL | "reference interval" |
| above 912.6 ng/mL | No name given |
Derived the same way, printed as 435 to 2,067 nmol/L and converted here. The study included 637 women and 506 men [6].
What has been shown to move it
Shown to raise it1
Methylfolate in place of folic acid
Shown to raise blood folate and lower unmetabolized folic acid more than folic acid in women of childbearing age. These are blood markers, not health outcomes.
Red blood cell folate rose 23% and 31%.
The numbers and sources
- Effect
- Over 24 weeks, 113 µg a day of L-methylfolate lowered homocysteine 14.6% and 100 µg of folic acid 9.3% against placebo. Red blood cell folate rose 23% and 31% [8]. A 2025 meta-analysis of 11 RCTs in women of childbearing age found that active folate, compared with folic acid, raised plasma folate (p 0.04) and red blood cell folate (p 0.01) and lowered unmetabolized folic acid (p below 0.0001), with no difference in homocysteine or B12. In women with a history of adverse pregnancy outcomes, it was linked to higher later pregnancy rates and fewer adverse outcomes [9]. A 2026 systematic review found that 5-MTHF in place of folic acid reduced unmetabolized folic acid in 3 trials (SMD 0.99, 95% CI 0.20 to 1.79, GRADE low), and showed no difference in homocysteine [10]. A 2024 review reported a lack of clinical studies testing methylfolate for preventing neural tube defects [11].
- Population
- 167 healthy volunteers [8]; women of childbearing age in 11 RCTs [9]; trials and observational studies in two reviews [10][11].
- Sources
- [8], [9], [10], [11]
- Caveats
- Most results are blood markers, not health outcomes. The 2025 meta-analysis notes low study quality and short treatment [9]. The 2026 review found the two trials of red blood cell folate pointed in opposite directions, and found no evidence that unmetabolized folic acid causes harm on its own. Its authors disclosed ties to a company developing a folinic acid drug [10]. [11] is a narrative review funded by ITF Research Pharma.
How it compares with the reference method
Mixed results1
Red cell folate against serum folate
Limited evidence: two reviews and a British guideline judged that red cell folate adds little to serum folate for detecting deficiency.
The numbers and sources
- Compared with
- Serum folate
- Effect
- A review found that red cell folate measurements, and not serum folate, varied with sample pretreatment, the oxygen saturation of hemoglobin and the hematocrit. Neither marker was clearly superior in characterizing deficiency, and serum folate more often showed the higher correlation with homocysteine. A common variant of the MTHFR gene alters the forms of folate in red cells and may add to the variability of routine red cell assays [12]. A review of laboratory practice in the United Kingdom concluded from the literature that serum folate provides equivalent information to red cell folate in determining whether deficiency is present [13]. A 2014 British hematology guideline states that serum folate offers equivalent diagnostic capability and is the first-line test [14].
- Population
- Narrative reviews of published studies, one with workload data from United Kingdom hematology laboratories from 1999 to 2002 [12][13].
- Sources
- [12], [13], [14]
- Caveats
- Neither review pooled data. Serum folate reflects recent intake and red cell folate the longer term, so the two answer different questions and are reported on different scales [2].
Did not match the reference method1
Agreement between assay types
Limited evidence: one protein-binding assay read about 30% lower than reference methods, and cut-offs applied across assays misclassified folate status in US survey data.
The numbers and sources
- Compared with
- Microbiological assay and liquid chromatography-tandem mass spectrometry
- Effect
- WHO reports that protein-binding assays were found to be less accurate, with one measuring about 30% lower red cell and serum folate than the microbiological assay and mass spectrometry, and that microbiological assays in three laboratories gave different results depending on the calibrator or microorganism used [2]. In US survey data from 1988 to 1994, the share of people under the red cell cut-off for risk of deficiency was 7.4% when the cut-off matched the assay and 28% when it did not. For possible deficiency the figures were 37% and 84%, and in 1999 to 2006 they were 4.8% and 53% [4].
- Population
- Method comparison studies summarized by WHO [2]. Participants aged 4 and older in US national surveys from 1988 to 2010 [4].
- Sources
- [2], [4]
- Caveats
- WHO summarizes the comparisons without giving sample sizes. The survey authors state that the confusion likely applies to clinical assays as well [4]. A result near a cut point may be classed differently on another assay.
What studies tie it to
Linked in research2
Neural tube defects in pregnancy
Linked to fewer neural tube defects at higher levels in early pregnancy, an estimated 25 per 10,000 births at about 221 ng/mL and 6 at about 521.
The numbers and sources
- Effect
- In a case-control study, a woman's risk of having a child with a neural tube defect was associated with early pregnancy red cell folate in a continuous dose-response relationship [7]. A model built on two Chinese studies of folic acid 400 µg a day estimated 25.4 defects per 10,000 births (95% uncertainty interval 20.8 to 31.2) at a red cell folate of 500 nmol/L (about 221 ng/mL) and 6 per 10,000 at 1,180 nmol/L (about 521 ng/mL). Risk was substantially attenuated above about 1,000 nmol/L (about 442 ng/mL) [8]. WHO sets above 400 ng/mL as the population threshold for women of reproductive age [2].
- Population
- Women in a case-control study of early pregnancy blood samples [7]. 247,831 participants in a Chinese community intervention and 1,194 in a randomized trial of folic acid [8].
- Sources
- [7], [8], [2], [5]
- Caveats
- The model combines an intervention project with a separate trial that measured blood folate, so the link between a red cell level and risk is estimated, not observed in the same women [8]. WHO states that its threshold is for populations and is not to be used to predict an individual's risk, since low folate is not responsible for all neural tube defects [2]. The cut points depend on the assay [5]. The ng/mL figures are converted here from nmol/L.
Cardiovascular death in adults with hypertension
Limited evidence: two US survey analyses linked the highest red cell folate levels to more cardiovascular deaths in adults with hypertension.
The numbers and sources
- Effect
- In adults with hypertension surveyed from 1991 to 1994, the high folate quartile had a hazard ratio for cardiovascular death of 1.44 (95% CI 1.31 to 1.58) against the intermediate quartiles and 2.13 (1.77 to 2.57) for death from heart attack. The low quartile did not differ (1.09, 0.94 to 1.27) [9]. In adults with hypertension surveyed from 1999 to 2014, the highest quartile against the second had hazard ratios of 1.68 (1.30 to 2.16) for cardiovascular death and 1.30 (1.16 to 1.46) for death from any cause, and the lowest quartile was not associated with either. The associations were non-linear, with inflection points at 819.7 and 760.1 ng/mL [10].
- Population
- 2,986 US adults with hypertension, 579 cardiovascular deaths over an average 11.7 years [9]. 13,986 US adults with hypertension, 548 cardiovascular deaths over a median 7.0 years [10].
- Sources
- [9], [10]
- Caveats
- Observational, and limited to people with hypertension. Supplement use and illness may differ between people with high and low levels. No trial cited here tested the outcome of lowering a high red cell folate [9][10].
Checked, no link found1
Colorectal cancer
Limited evidence: one US study of postmenopausal women found red cell folate was not linked to colorectal cancer.
The numbers and sources
- Effect
- The odds ratio for colorectal cancer in the highest against the lowest quarter of red cell folate was 0.91 (95% CI 0.67 to 1.24), and the same comparison for plasma folate gave 0.91 (0.67 to 1.23). The results did not change across the periods before, during and after folic acid fortification of the US food supply [11].
- Population
- 988 women with colorectal cancer and matched controls, drawn from 93,676 postmenopausal women aged 50 to 79 in the Women's Health Initiative Observational Study [11].
- Sources
- [11]
- Caveats
- Observational, in postmenopausal women only, with folate measured once at enrollment [11].
Related
Sources
- US Food and Drug Administration. 21 CFR 862.1295, Folic acid test system. Electronic Code of Federal Regulations. https://www.ecfr.gov/current/title-21/section-862.1295
- World Health Organization. Serum and red blood cell folate concentrations for assessing folate status in populations. Vitamin and Mineral Nutrition Information System. Geneva: World Health Organization, 2015. WHO/NMH/NHD/EPG/15.01. https://iris.who.int/handle/10665/162114
- Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academies Press. 1998. https://doi.org/10.17226/6015
- Pfeiffer CM, Sternberg MR, Hamner HC, et al. Applying inappropriate cutoffs leads to misinterpretation of folate status in the US population. The American Journal of Clinical Nutrition. 2016. https://doi.org/10.3945/ajcn.116.138529
- Tinker SC, Hamner HC, Qi YP, Crider KS. U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012. Birth Defects Research Part A: Clinical and Molecular Teratology. 2015. https://doi.org/10.1002/bdra.23378
- Risch M, Meier DW, Sakem B, et al. Vitamin B12 and folate levels in healthy Swiss senior citizens: a prospective study evaluating reference intervals and decision limits. BMC Geriatrics. 2015. https://doi.org/10.1186/s12877-015-0060-x
- Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate Levels and Neural Tube Defects: Implications for Prevention. JAMA. 1995. https://doi.org/10.1001/jama.1995.03530210052030
- Crider KS, Devine O, Hao L, et al. Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ. 2014. https://doi.org/10.1136/bmj.g4554
- Twum F, Morte N, Wei Y, et al. Red blood cell folate and cardiovascular deaths among hypertensive adults, an 18-year follow-up of a national cohort. Hypertension Research. 2020. https://doi.org/10.1038/s41440-020-0482-5
- Xu J, Zhu X, Guan G, et al. Non-linear associations of serum and red blood cell folate with risk of cardiovascular and all-cause mortality in hypertensive adults. Hypertension Research. 2023. https://doi.org/10.1038/s41440-023-01249-3
- Neuhouser ML, Cheng TY, Beresford SA, et al. Red blood cell folate and plasma folate are not associated with risk of incident colorectal cancer in the Women's Health Initiative observational study. International Journal of Cancer. 2015. https://doi.org/10.1002/ijc.29453
- Farrell CJ, Kirsch SH, Herrmann M. Red cell or serum folate: what to do in clinical practice? Clinical Chemistry and Laboratory Medicine. 2013. https://doi.org/10.1515/cclm-2012-0639
- Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology Alliance benchmarking review. Journal of Clinical Pathology. 2003. https://doi.org/10.1136/jcp.56.12.924
- Devalia V, Hamilton MS, Molloy AM, British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. British Journal of Haematology. 2014. https://doi.org/10.1111/bjh.12959