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Longevity Library · Lab reference

Written by Daniel Tagge, MD
Updated October 10, 2026
Reviewed October 12, 2026
38 sources · Measured in ng/mL

System: Epigenetics

FolateSerum folate · Red blood cell folate · Vitamin B9

A serum folate below about 3 to 4 ng/mL is deficient on either standard definition and fewer than 1 in 100 Americans have been there since grain fortification; above that the serum number mostly reports recent intake, moving with the hours since the last meal or pill and falling within weeks without one, so red-cell folate is the measure of stores and the only folate threshold with an outcome behind it (above 400 ng/mL for neural tube defects); no trial has shown a benefit from pushing a replete serum folate higher, and a high folate beside an unmeasured B12 is the combination to avoid, because in B12-deficient people homocysteine and methylmalonic acid rose, not fell, as folate climbed.

Folate is the carrier of the one-carbon units that methylate DNA and build its building blocks, and the serum level is a rough proxy for recent intake. Laboratories flag deficiency below about 3 to 4 ng/mL, a value that has become rare in fortified countries, and print no upper limit. Above repletion the evidence thins: folic acid lowered homocysteine by about a quarter in trials and prevented some strokes but no heart attacks, had no effect on cancer at five years, and a high folate helped or harmed depending on whether B12 was adequate. Red-cell folate reflects months of intake and is the test that predicts neural tube defects.

01 · The scale

Where the laboratory range and the evidence sit.

Deficiency, defined by anemia or by a rising homocysteine, sat below about 3 to 4 ng/mL and has been rare in the United States since grain fortification; the protective threshold for neural tube defects was a red-cell folate above 400 ng/mL; folic acid lowered homocysteine by about a quarter in trials and prevented some strokes and no heart attacks, with no effect on cancer over five years; and a high serum folate was helpful or harmful depending on B12, with anemia and cognitive impairment about three times as likely when folate was high and B12 low.

0510152025

  1. Common laboratory reference range (lower limit printed about 3 to 4; no upper limit)

    3 and above ng/mL · Typical US laboratories; Jacques 1999; Pfeiffer 2012

  2. Deficient on the anemia-based cut-off (about 3 ng/mL, 7 nmol/L): 22 percent of Framingham non-supplement users before fortification, 1.7 percent after

    0 to 3 ng/mL · Jacques 1999; Odewole 2013

  3. Low on the homocysteine-based cut-off (10 nmol/L, about 4 ng/mL): 1 percent or less of Americans since fortification

    3 to 4.4 ng/mL · Pfeiffer 2012; WHO (Cordero 2015)

  4. Replete: with B12 above 148 pmol/L, homocysteine and methylmalonic acid fell as serum folate rose across this range

    4.4 and above ng/mL · Selhub 2007 (NHANES)

  5. Where US adults sit: mean about 10 in non-supplement users after fortification, median about 15 in adults over 50

    10 to 15 ng/mL · Jacques 1999; Odewole 2013

  6. With B12 below 148 pmol/L, homocysteine and methylmalonic acid rose as folate climbed above about 9 ng/mL (20 nmol/L); above about 26 (59 nmol/L), anemia and cognitive impairment 3.1 and 2.6 times as likely

    9 and above ng/mL · Selhub 2007; Morris 2007

  • Laboratory range
  • Evidence supports
  • Guideline goal or unstudied
  • Higher risk in studies
Scale in ng/mL. Some reports print nmol/L: multiply ng/mL by about 2.27. Red-cell folate is a separate test, reported in ng/mL or µg/L (the same number) and running in the hundreds. Bands show where studies found something, not a recommendation for any one person.

02 · What it is

What Folate measures.

On a metabolomic panel folate is read as the carrier in a network, not as a level. Folate-mediated one-carbon metabolism supports the synthesis of purines and thymidine for DNA, the balance of glycine, serine and methionine, the maintenance of epigenetic marks and redox defense, and it is compartmentalized between mitochondria and cytosol and across organs. Almost all the folate in human plasma travels as 5-methyltetrahydrofolate, which must give its methyl group to homocysteine, through the B12-dependent enzyme methionine synthase, before a cell can retain it. That is why a shortage of B12 traps folate in its methyl form, why folate deficiency raises homocysteine, and why homocysteine, not the serum folate, is the functional readout of the folate side of the cycle.1,2,3Grade A

Folate, also called vitamin B9, is a family of compounds required in the diet, with the tetrahydro forms biologically active. Detecting and correcting deficiency prevents megaloblastic anemia and reduces the risk of neural tube defects; coexisting deficiencies of folate and B12 are associated with cognitive decline, depression and neuropathy; and both deficiency and excess have been implicated in some cancers. Three laboratory markers exist: total folate in serum or plasma, which most laboratories use; folate in red cells, which is fixed when the cells are made and so reflects status over the preceding four months or so; and homocysteine, which reflects the cellular use of folate and B12 together.3,4Grade A

The two folate tests differ in what they report and in how they misbehave. Serum folate is cheaper and faster, is influenced by fewer analytical variables and, in a review of the comparative studies, correlated with homocysteine more often than red-cell folate did. Red-cell folate varies with sample pre-treatment, the oxygen saturation of hemoglobin and the hematocrit, and the common MTHFR 677 variant changes the mix of folate forms inside red cells, which adds assay variability. Both rise with supplementation, serum generally more and in proportion to the dose. The British haematology guideline calls serum folate diagnostically equivalent to red-cell folate and makes it the first-line test.5,6Grade A

Cut-offs for deficiency were first set at the concentrations below which macrocytic anemia appears, about 3 ng/mL (7 nmol/L) in serum, and were later revised using homocysteine as the metabolic indicator, to a serum folate below 10 nmol/L (about 4 ng/mL) and a red-cell folate below 340 nmol/L (about 150 ng/mL). The WHO adds a third threshold with a different purpose: a red-cell folate above 400 ng/mL (906 nmol/L) in women of reproductive age, below which the risk of a neural-tube-defect pregnancy rises at the population level.7,8,9Grade A

03 · Origins

Where it came from, and where it sits in the network.

Folate is built from GTP. Bacteria carry the pathway from GTP, through a pterin ring joined to para-aminobenzoate and glutamate, to dihydrofolate, and the structures of nearly all its enzymes are known because the pathway is a target for antibiotics. Plants synthesize folates de novo and are the main dietary source for humans, and comparative genomics across hundreds of bacterial genomes and the Arabidopsis genome shows the plant pathway assembled from prokaryotic homologs, down to a transporter and a missing synthesis gene predicted and then confirmed in the laboratory. Animals do not have the pathway and must take the cofactor in the diet, which is why folate is a vitamin for us and a metabolite for a leaf.10,11,12Grade C

One hypothesis ties folate to the color of human skin. In 1978 Branda and Eaton showed that simulated strong sunlight destroyed 30 to 50 percent of the folate in human plasma within 60 minutes and that light-skinned patients treated with ultraviolet light had abnormally low serum folate, and proposed that dark pigmentation was maintained in regions of intense sunlight partly to protect folate, whose deficiency causes anemia, fetal loss and infertility. Jablonski and Chaplin later showed skin reflectance tracking ultraviolet levels across indigenous populations and framed pigmentation as a compromise between protecting folate, which ultraviolet radiation and the reactive oxygen species generated by UVA destroy, and making vitamin D, which needs UVB; depigmented skin evolved several separate times as people moved to low-UVB latitudes. It remains a hypothesis resting on correlation and a plausible mechanism, not a tested cause.13,14,15Grade C

On the shelf, folate is the carrier of the one-carbon network, Vitamin B12 the cofactor of the enzyme that transfers the carbon to homocysteine, and MTHFR the enzyme that makes the methyl form; homocysteine is the shared readout. Low folate raises homocysteine and leaves methylmalonic acid alone, because methylmalonic acid belongs to B12's other enzyme, so a raised homocysteine with a normal methylmalonic acid points at folate. A high serum folate reads differently depending on B12: in about 10,000 US adults across two national surveys, homocysteine and methylmalonic acid both fell as folate rose when B12 was above 148 pmol/L, but when B12 was lower both metabolites rose as folate climbed beyond about 20 nmol/L (about 9 ng/mL), which the authors read as a worsening of B12's enzymatic functions as folate status increases. The methyl trap behind that interaction is also the proposed reason folic acid can precipitate or worsen the spinal cord disease of pernicious anemia, and it is why folate is never read alone on this shelf.16,2,1Grade B

04 · The laboratory range

What a laboratory calls normal.

Serum folate above about 3 to 4 ng/mL printed as normal, with no upper limit flagged on most reports; red-cell folate above about 150 ng/mL (340 nmol/L).

Fortification reset the distribution. In the Framingham Offspring cohort, among 350 people examined after US grain fortification (140 micrograms of folic acid per 100 g, complete by mid-1997) who took no supplements, mean plasma folate rose from 4.6 to 10.0 ng/mL and the share below 3 ng/mL fell from 22.0 to 1.7 percent, while 756 people examined before fortification did not change. In the national survey, assay-adjusted serum folate after fortification was 2.5 times and red-cell folate 1.5 times the pre-fortification level; the share with a low serum folate (below 10 nmol/L) or red-cell folate (below 340 nmol/L) was 1 percent or less in every demographic subgroup, against 24 percent and 3.5 percent before, and concentrations then drifted down by 17 percent (serum) and 12 percent (red cell) over the following 12 years.9,8Grade B

A printed 'low' is now a finding that asks for a reason. In a random sample of 1,546 Americans aged 50 and over from the REGARDS cohort, the median serum folate was 15.1 ng/mL (34.2 nmol/L), 2 of 1,546 (0.1 percent) were deficient below 3.0 ng/mL, and folate-deficiency anemia was found in 1 person. Supplements add to the fortified baseline: in 2,734 national-survey samples, the geometric mean of 5-methyltetrahydrofolate was 48.4 nmol/L (about 21 ng/mL) in supplement users and 30.7 nmol/L (about 14 ng/mL) in non-users.17,18Grade B

The assay changes the number. The microbiologic assay produces higher concentrations than the radioassay it replaced in the national survey and is considered more accurate, which is why the survey's older results had to be adjusted before trends could be read; the WHO recommends the microbiological assay as the most reliable way to obtain comparable red-cell folate results across countries. Protein-binding assays also exaggerated the MTHFR genotype differences in serum (20 percent between CC and TT against 13 percent by the microbiologic assay) and failed to show the pattern at all in red cells. A folate from one laboratory is not interchangeable with a folate from another.8,7,19Grade A

05 · The evidence

What the studies support.

The one folate threshold with a hard outcome behind it is for red cells, not serum. In an Irish case-control study, a woman's risk of a neural-tube-defect pregnancy fell continuously as her early-pregnancy red-cell folate rose, and the authors calculated that the standard 0.4 mg a day of folic acid would prevent 48 percent of cases. A Bayesian model built on 247,831 participants in a Chinese community intervention and 1,194 women in a randomized trial reproduced that curve: 25.4 neural tube defects per 10,000 births at a red-cell folate of 500 nmol/L (about 220 ng/mL), falling to 6 per 10,000 at 1,180 nmol/L (about 520 ng/mL), with the risk substantially attenuated above about 1,000 nmol/L. On that evidence the WHO set its population threshold at a red-cell folate above 400 ng/mL (906 nmol/L) for women of reproductive age, recommended no serum threshold, and noted that 22.8 percent of US women of childbearing age were below the cut-off in 2007 to 2012; US neural tube defect prevalence fell from 10.7 to 7.0 per 10,000 live births after fortification, about 1,326 fewer affected infants a year.20,21,7Grade A

The trials behind that threshold are among the clearest in nutrition. In the Medical Research Council trial, 1,817 women who had already had an affected pregnancy were randomized to folic acid, other vitamins, both or neither; of 27 neural tube defects in 1,195 completed pregnancies, 6 occurred in the folic acid groups and 21 in the others, a 72 percent protective effect (relative risk 0.28), while the other vitamins did nothing. In 121 Irish women with a red-cell folate of 150 to 400 µg/L, six months of 100, 200 or 400 micrograms of folic acid a day raised the median to 375, 475 and 571 µg/L, so even the lowest dose moved most women toward the protective range. The US Preventive Services Task Force reaffirmed in 2023, with high certainty, that everyone planning or able to become pregnant should take 0.4 to 0.8 mg of folic acid a day; about 3,000 US pregnancies a year are affected.22,23,24Grade A

For homocysteine the dose-response is settled. Pooling individual data from 25 randomized trials and 2,596 people, and standardizing to a starting homocysteine of 12 µmol/L and folate of 12 nmol/L, daily folic acid at 0.2, 0.4, 0.8, 2.0 and 5.0 mg lowered homocysteine by 13, 20, 23, 23 and 25 percent; 0.8 mg a day gives the maximal effect, 0.4 mg about 90 percent of it and 0.2 mg about 60 percent, with larger reductions in people who started with higher homocysteine or lower folate. Adding about 0.4 mg of B12 took off a further 7 percent and B6 added nothing. Population fortification at a far smaller dose moved the Framingham mean from 10.1 to 9.4 µmol/L and halved the share above 13 (18.7 to 9.8 percent).25,9Grade A

Lowering homocysteine with folic acid changed one outcome. Across 15 randomized trials and 71,422 people, B vitamins did not change heart attacks (risk ratio 1.02) or deaths (1.01) and reduced stroke from 5.1 to 4.3 percent (0.90), all rated high-quality evidence. The clearest folic-acid-only result came from China, where grain is not fortified: 20,702 adults with hypertension and no prior stroke or heart attack took enalapril with or without 0.8 mg of folic acid for a median 4.5 years, and first stroke fell from 3.4 to 2.7 percent (hazard ratio 0.79) with no change in heart attack (1.04) or death (0.94), a benefit the authors tie to low baseline folate. The homocysteine entry on this shelf carries the full trial record, including why the benefit disappears in fortified populations.26,27Grade A

Folate's relation to cancer runs both ways, and the trials have to be read carefully. In the Aspirin/Folate Polyp Prevention Study, 1,021 people with a recent colorectal adenoma were randomized to 1 mg of folic acid a day or placebo; after three years the adenoma recurrence was 44.1 versus 42.4 percent (risk ratio 1.04), and among the 607 who had a second colonoscopy three to five years later advanced lesions were found in 11.6 versus 6.9 percent (risk ratio 1.67, p=0.05), with more people having three or more adenomas and more non-colorectal cancers on folic acid. But pooling individual data from all 13 trials of at least a year and 500 people, 49,621 participants over an average 5.2 years, folic acid quadrupled plasma folate (57.3 versus 13.5 nmol/L, about 25 versus 6 ng/mL) and did not significantly change overall cancer incidence (1,904 versus 1,809 cancers, rate ratio 1.06, 95 percent CI 0.99 to 1.13) or the incidence at any site, including the large intestine; the doses in those trials were on average an order of magnitude above what fortification delivers. Five years is the limit of that reassurance.28,29Grade A

At the high end the question is always the B12. In 1,459 Americans aged 60 and over surveyed after fortification, low B12 status (serum B12 below 148 pmol/L or methylmalonic acid above 210 nmol/L) carried 2.7 times the odds of anemia and 2.5 times the odds of cognitive impairment; within that low-B12 group, a serum folate above 59 nmol/L (about 26 ng/mL, the 80th percentile) carried 3.1 times the odds of anemia and 2.6 times the odds of cognitive impairment compared with a lower folate, while in people with normal B12 the same high folate went with less cognitive impairment (odds 0.4). The metabolite data from the same surveys show the mechanism: with B12 adequate, homocysteine and methylmalonic acid fell as folate rose; with B12 low, both rose from a folate of about 20 nmol/L (about 9 ng/mL) upward. Cross-sectional data, and the authors note that an experiment would be unethical, but the direction matches the 1981 account of the methyl trap.30,16,2Grade C

Folic acid itself, the synthetic form, now circulates in nearly everyone. In the 2007 to 2008 national survey, unmetabolized folic acid was detectable in more than 95 percent of 2,707 serum samples from supplement users and non-users alike, exceeded 1 nmol/L in 33.2 percent overall and in 21.0 percent of adults fasting 8 hours or more, and tracked with total folic acid intake, a shorter fast, older age and higher red-cell folate. The appearance threshold had been set in 1997: unaltered folic acid appeared in serum once a meal delivered about 266 micrograms, and above 200 micrograms from a tablet. In 105 postmenopausal women, folic acid was detectable in fasting plasma in 78 percent and natural killer cell cytotoxicity was about 23 percent lower where it was found, a small cross-sectional signal that has not been tested in a trial. What chronic exposure means for health is an open question, not an established harm.18,31,32Grade C

06 · What moves it

The levers with evidence behind them.

What is listed here has been tested. The size of each effect, and the size of the study, are in the sentence, so a small effect reads as a small effect.

  • Vegetables and citrus fruit

    raise it; food folate works nearly as well as a tablet

    In a 4-week controlled feeding trial, 66 healthy adults were fed a diet high in vegetables and citrus fruit (about 560 micrograms of folate a day), a low-folate diet (about 210 micrograms) plus 250 micrograms of folic acid a day, or the low-folate diet plus placebo; folate status improved and homocysteine fell in both the food-folate and the folic-acid groups, and the bioavailability of the food folate worked out at 60 to 98 percent of folic acid depending on the endpoint. Folate takes its name from the leaf.33Grade B

  • Fortified grain

    raises it; the reason deficiency is now rare in the United States

    Adding 140 micrograms of folic acid per 100 g of enriched grain doubled mean plasma folate in Framingham non-supplement users (4.6 to 10.0 ng/mL) and cut the share below 3 ng/mL from 22.0 to 1.7 percent within a year of full implementation. Nationally, serum folate rose 2.5-fold and red-cell folate 1.5-fold, and low values fell to 1 percent or less. A person who eats no enriched grain, bread, pasta, rice or cereal, by choice or by a gluten-free or low-carbohydrate pattern, has opted out of that baseline and depends on vegetables, legumes or a supplement instead.9,8Grade A

  • Folic acid supplements, by dose

    raise serum folate within weeks and red-cell folate over months

    In 121 women starting with a red-cell folate of 150 to 400 µg/L, six months of 100, 200 or 400 micrograms a day produced median increments of 67, 130 and 200 µg/L. In 144 women aged 19 to 33, plasma folate plateaued after 12 weeks on 400 micrograms a day while red-cell folate was still rising at 24 weeks, which is why a serum value reflects the last few weeks and a red-cell value the last few months, and why pre-conception supplementation needs longer than four weeks to fill the red cells. For homocysteine, 0.8 mg a day gives the maximal reduction and 0.4 mg about 90 percent of it; more is not more.23,34,25Grade A

  • Methylfolate versus folic acid

    the natural form raised red-cell folate more in one trial; no outcome has been compared

    In a 24-week randomized trial of 144 women, 416 micrograms a day of [6S]-5-methyltetrahydrofolate (the form that circulates in blood) raised red-cell folate more than the equimolar 400 micrograms of folic acid, and half that dose of methylfolate did less than either. That trial measured blood folate, not births or any clinical outcome; every trial that prevented neural tube defects, and the fortification that lowered their prevalence, used folic acid. Folic acid differs in one measurable way: above about 200 micrograms in a dose it appears unaltered in serum, and it is now detectable in more than 95 percent of Americans. Which form a person takes matters less than the dose, the duration before conception, and whether B12 is adequate, and it is a conversation for a prescriber rather than a product claim.34,22,31,18Grade B

  • Alcohol

    lowers it by cutting absorption, liver uptake and kidney conservation

    Thirty years of studies by one group found intestinal absorption of folic acid decreased in binge-drinking alcoholics and, prospectively, in volunteers fed alcohol with low-folate diets; in monkeys fed alcohol for two years, liver folate stores fell, absorption fell and urinary loss rose, and in pigs the alcohol lowered the intestinal folate carrier. Folate deficiency in turn accelerated alcohol's damage to liver methionine metabolism. The human data are small and the mechanism comes from animals, but the direction is consistent, and alcohol is on the classic list of agents that produce low serum and tissue folate.35,4Grade C

  • Medications

    several classes lower it, one class by design

    Folate antagonists, among them some chemotherapy, antimalarial, antibiotic and diuretic drugs, block the enzyme that activates dietary folate and readily cause megaloblastic anemia, which folinic acid prevents; anticonvulsants, some tuberculosis drugs and oral contraceptives lower serum and tissue folate by mechanisms that are uncertain (reduced absorption, altered protein binding or faster liver metabolism have been proposed), and megaloblastic anemia on anticonvulsants is rare, under 0.75 percent. Whether a medicine should change is the prescriber's call, never a reason to stop on one's own.4Grade B

  • Pregnancy, planned or possible

    raises the requirement; the one situation with a trial-proven target

    The neural tube closes in the first month, often before a pregnancy is known, which is why the US Preventive Services Task Force recommends 0.4 to 0.8 mg of folic acid a day for everyone planning or able to become pregnant, and why the red-cell folate, which takes months to fill, is the number that matters. In the Irish dose trial, 400 micrograms a day took the median red-cell folate from the 150 to 400 µg/L entry range to 571 µg/L in six months; a woman who starts the week she learns she is pregnant has missed most of that window.24,7,23,34Grade A

  • MTHFR 677 genotype

    lowers it by about a seventh in TT carriers; routine testing is not recommended

    Across 40 studies of women aged 12 to 49, using the microbiologic assay, women with two copies of the MTHFR 677T variant ran 13 percent lower serum folate and 16 percent lower red-cell folate than CC women, with one copy in between. The American College of Medical Genetics concluded in 2013 that MTHFR polymorphism testing has minimal clinical utility and should not be part of a routine evaluation, because meta-analyses had disproven the links from the variant through homocysteine to coronary disease and venous thrombosis. Measuring folate, B12 and homocysteine captures what the genotype would predict; the homocysteine entry covers the one specific lever (riboflavin) for people who already know they are TT.19,36Grade B

07 · Reading it well

Caveats, and what belongs with a physician.

Timing decides the serum number. Serum 5-methyltetrahydrofolate and unmetabolized folic acid both differed significantly by hours since the last meal in the national survey, and folic acid appears unaltered in serum within the hours after a meal delivering more than about 200 to 266 micrograms, so a sample drawn after breakfast cereal or a multivitamin reads higher than a fasting one. In the other direction, 8 women housed in a metabolic unit and fed 56 micrograms of folate a day developed a subclinical deficiency with decreased plasma folate, raised homocysteine and lymphocyte DNA hypomethylation within the first five weeks, reversed by 286 to 516 micrograms a day. Red-cell folate, fixed when the cells are made, reflects the preceding four months or so. Draw fasting, before starting a supplement, and read serum as recent and red cell as stored.18,31,37,3Grade B

Hemolysis raises serum folate, because red cells hold far more folate than serum does. In a study of 45 analytes on one manufacturer's analyzers, folate was the third most hemolysis-sensitive after lactate dehydrogenase and aspartate aminotransferase, and under 5 percent of hospital samples were affected by more than 10 percent. A surprisingly high serum folate from a difficult draw or a sample that sat is a reason to repeat it, and a high folate is never a reason for alarm on its own.38Grade C

Red-cell folate has analytical problems of its own: the result varies with sample pre-treatment, the oxygen saturation of hemoglobin and the hematocrit, poor stability, polyglutamate chain length and unreliable extraction make the analysis challenging, and the MTHFR 677 variant changes the distribution of folate forms inside red cells. Protein-binding assays and the microbiologic assay disagree by amounts large enough to shift a national prevalence estimate, which is why the WHO names the microbiological assay as the comparable method and why a result should be read against the issuing laboratory's own range rather than a number on a page.5,3,7,19Grade A

A high folate asks for a B12 before anything else. Folic acid given in B12 deficiency corrects the anemia while the spinal cord disease progresses, the classic masking that the methyl trap explains and that the fortification debate was about; the laboratory guidance is that a high folate status should be followed by an assessment of B12 status, a review of previous results and a look at the supplement regime. The haematology guideline adds that when strong clinical features of deficiency conflict with a test result, treatment should not wait. The Vitamin B12 entry on this shelf carries the methylmalonic acid logic that settles an indeterminate B12.2,3,6,31Grade A

Homocysteine is the companion number, and it moves before the blood count does. In the metabolic-unit depletion study, homocysteine rose during the low-folate weeks while no anemia developed, and the dose-response trials show it falling in proportion to folate up to 0.8 mg a day. A folate in the normal range with a raised homocysteine points at B12, riboflavin status, kidney function or a medication rather than at more folate; the homocysteine entry carries what lowering it did and did not do in trials.37,25,26Grade A

The genotype is context, not alarm. The MTHFR 677TT genotype lowers blood folate by roughly a seventh in women on the microbiologic assay and has no recommended role in routine testing; a person who knows the genotype needs the same three numbers as everyone else (folate, B12 with methylmalonic acid, homocysteine), read together.19,36Grade B

See a physician

  • Anemia, especially with large red cells, at any folate value: the B12 and methylmalonic acid must be known before folic acid is started, because folic acid can correct the blood count while an unrecognized B12 deficiency damages the nerves.
  • A low folate, or a red-cell folate below about 400 ng/mL, in anyone pregnant or planning a pregnancy, where the dose and the timing before conception both matter and the window is the first month.
  • Numbness or tingling, trouble with balance, or memory or mood change alongside a normal or high folate and an untested B12.
  • Heavy alcohol use together with a low folate or an anemia, which usually means absorption and liver handling are both impaired and the folate is one of several problems.
  • A low folate while taking a folate antagonist, an anticonvulsant or another medicine on the list above, so the prescriber can weigh replacement or a change.
  • A folate that stays low on an ordinary diet including fortified grain, which raises the question of absorption and belongs with a workup rather than a bigger tablet.

This page is education, not individual medical advice, and reading it creates no physician-patient relationship.

08 · Open questions

What the literature does not settle.

  • No trial has treated a replete, symptom-free adult to a higher serum folate target and measured an outcome; above about 4 ng/mL every serum number is cohort association or a homocysteine effect, and an optimal serum folate is undefined.
  • Whether long-term high folic acid intake carries risk is unresolved: one adenoma trial saw more advanced lesions on 1 mg a day, the pooled trials saw no cancer effect over five years at doses an order of magnitude above fortification, unmetabolized folic acid is now detectable in nearly everyone, and no trial has run long enough to answer the question that matters.
  • Whether methylfolate differs from folic acid in any clinical outcome has not been tested; the comparisons measured blood folate, and the trials that prevented neural tube defects used folic acid.
  • Whether serum or red-cell folate should be the standard test for an individual is still argued, with the haematology guideline calling them equivalent for diagnosing deficiency and the WHO declining to set any serum threshold for neural tube defect prevention.
  • Why folic acid prevented stroke and not heart attack, and whether the folate status of the population is the whole explanation, is carried as an open question on the homocysteine entry.

10

Questions

11 · Sources

38 sources, read in full.

Numbered in the order they appear. Each line says what this page relies on from the paper; the link opens the record at PubMed or the publisher.

  1. 1.

    Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metabolism. 2017. PMID 27641100. DOI 10.1016/j.cmet.2016.08.009.

    Review · Folate-mediated one-carbon metabolism supports purine and thymidine synthesis, glycine, serine and methionine homeostasis, epigenetic maintenance and redox defense, and is compartmentalized within cells and across organs, with mitochondrial reactions supplying one-carbon units, glycine and NADPH.

  2. 2.

    Scott JM, Weir DG. The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet. 1981. PMID 6115113. DOI 10.1016/s0140-6736(81)90650-4.

    Review · 5-methyl-THF, the form in which almost all folate travels in human plasma, must react with intracellular homocysteine (via methionine synthetase) before a cell can retain it; in B12 deficiency folate is trapped in the methyl form, and folic acid, by driving cell division and methionine use, impairs myelin methylation and precipitates or exacerbates subacute combined degeneration.

  3. 3.

    Sobczyńska-Malefora A, Harrington DJ. Laboratory assessment of folate (vitamin B9) status. Journal of Clinical Pathology. 2018. PMID 30228213. DOI 10.1136/jclinpath-2018-205048.

    Review · Folate roles in nucleic acid synthesis, methyl group biogenesis and amino acid metabolism; deficiency correction prevents megaloblastic anemia and reduces NTD risk; coexisting folate and B12 deficiency associated with cognitive decline, depression and neuropathy; deficiency and excess implicated in some cancers; red-cell folate fixed during erythropoiesis and indicative of the preceding about 4 months; 5-methylTHF the main blood form; high folate should be followed by B12 assessment and review of supplementation.

  4. 4.

    Lambie DG, Johnson RH. Drugs and folate metabolism. Drugs. 1985. PMID 3896745. DOI 10.2165/00003495-198530020-00003.

    Review · Folates are required in the diet; aminopterin, methotrexate, pyrimethamine, trimethoprim and triamterene inhibit dihydrofolate reductase and produce deficiency; anticonvulsants, antituberculosis drugs, alcohol and oral contraceptives lower serum and tissue folate by uncertain mechanisms; megaloblastic anemia in under 0.75 percent on anticonvulsants; folinic acid prevents methotrexate-induced anemia.

  5. 5.

    Farrell CJ, Kirsch SH, Herrmann M. Red cell or serum folate: what to do in clinical practice?. Clinical Chemistry and Laboratory Medicine. 2013. PMID 23449524. DOI 10.1515/cclm-2012-0639.

    Review · Red-cell but not serum folate varied with sample pre-treatment, hemoglobin oxygen saturation and hematocrit; neither marker clearly superior for deficiency, but serum folate more often correlated with homocysteine and responded more to supplementation; MTHFR C677T alters folate forms in red cells; serum folate cheaper, faster and influenced by fewer analytical variables.

  6. 6.

    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. PMID 24942828. DOI 10.1111/bjh.12959.

    Guideline · Serum folate offers equivalent diagnostic capability to red-cell folate and is the first-line test of choice for folate status; when a test result conflicts with strong clinical features of deficiency, treatment should not be delayed.

  7. 7.

    Cordero AM, Crider KS, Rogers LM, Cannon MJ, Berry RJ. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. MMWR Morbidity and Mortality Weekly Report. 2015. PMID 25905896.

    Guideline · WHO 2015: red-cell folate above 400 ng/mL (906 nmol/L) in women of reproductive age at the population level (strong recommendation, low-quality evidence); no serum threshold recommended; microbiological assay recommended; deficiency cut-offs originally anemia-based, later revised using homocysteine; 22.8 percent of US women below the cut-off (NHANES 2007 to 2012); US NTD prevalence 10.7 to 7.0 per 10,000 after fortification, about 1,326 fewer affected infants a year.

  8. 8.

    Pfeiffer CM, Hughes JP, Lacher DA, et al.. Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010. Journal of Nutrition. 2012. PMID 22437563. DOI 10.3945/jn.111.156919.

    Cross-sectional study · Assay-adjusted NHANES: post-fortification serum folate 2.5 times and red-cell folate 1.5 times pre-fortification; low serum (below 10 nmol/L) or red-cell (below 340 nmol/L) folate 1 percent or less in every subgroup versus 24 and 3.5 percent before; 17 percent (serum) and 12 percent (red cell) decline over 12 post-fortification years; the microbiologic assay reads higher than the radioassay and is considered more accurate.

  9. 9.

    Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. New England Journal of Medicine. 1999. PMID 10320382. DOI 10.1056/NEJM199905133401901.

    Prospective cohort · Framingham Offspring: among 350 non-supplement users examined after fortification (140 µg per 100 g, complete by mid-1997), mean plasma folate rose from 4.6 to 10.0 ng/mL, the share below 3 ng/mL fell from 22.0 to 1.7 percent, homocysteine fell from 10.1 to 9.4 µmol/L and the share above 13 from 18.7 to 9.8 percent; no change in 756 controls examined before fortification.

  10. 10.

    Bermingham A, Derrick JP. The folic acid biosynthesis pathway in bacteria: evaluation of potential for antibacterial drug discovery. BioEssays. 2002. PMID 12111724. DOI 10.1002/bies.10114.

    Review · The bacterial folate biosynthesis pathway from GTP to dihydrofolate is a validated antibiotic target; crystal structures of all but one of its enzymes are known.

  11. 11.

    Hanson AD, Gregory JF 3rd. Folate biosynthesis, turnover, and transport in plants. Annual Review of Plant Biology. 2011. PMID 21275646. DOI 10.1146/annurev-arplant-042110-103819.

    Review · Folates are essential cofactors for one-carbon transfer reactions and are needed in the diets of humans and animals; plants are major sources of dietary folate; all the plant folate synthesis genes are now known and have been used to engineer folate-enriched crops.

  12. 12.

    de Crécy-Lagard V, El Yacoubi B, de la Garza RD, Noiriel A, Hanson AD. Comparative genomics of bacterial and plant folate synthesis and salvage: predictions and validations. BMC Genomics. 2007. PMID 17645794. DOI 10.1186/1471-2164-8-245.

    Laboratory method study · Comparative genomics across hundreds of bacterial genomes and Arabidopsis predicted novel GTP cyclohydrolase I and folylpolyglutamate synthase families, a trifunctional p-aminobenzoate synthesis gene, a missing plant folate synthesis gene (folQ), a folate transporter and the absence of a salvage enzyme from plants; genetic and biochemical tests confirmed the predictions.

  13. 13.

    Branda RF, Eaton JW. Skin color and nutrient photolysis: an evolutionary hypothesis. Science. 1978. PMID 675247. DOI 10.1126/science.675247.

    Laboratory method study · Simulated strong sunlight destroyed 30 to 50 percent of folate in human plasma within 60 minutes; light-skinned patients treated with ultraviolet light had abnormally low serum folate; proposed that dark pigmentation protects folate and other light-sensitive nutrients in regions of intense sunlight.

  14. 14.

    Jablonski NG, Chaplin G. The evolution of human skin coloration. Journal of Human Evolution. 2000. PMID 10896812. DOI 10.1006/jhev.2000.0403.

    Review · Skin reflectance correlates strongly with latitude and UV levels; pigmentation is a compromise between photoprotection and vitamin D synthesis; highly melanized skin protected against UV photolysis of folate, essential for neural tube development and spermatogenesis; depigmentation evolved as hominids left the tropics; pigmentation has changed more than once in human evolution.

  15. 15.

    Jablonski NG, Chaplin G. Human skin pigmentation as an adaptation to UV radiation. Proceedings of the National Academy of Sciences of the United States of America. 2010. PMID 20445093. DOI 10.1073/pnas.0914628107.

    Review · Within the tropics the primary selective pressure was to protect folate by maintaining dark pigmentation; photolysis of folate and its main serum form 5-methyltetrahydrofolate is caused by UVR and by reactive oxygen species generated by UVA; depigmented and tannable skin evolved numerous times via independent genetic pathways under positive selection.

  16. 16.

    Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proceedings of the National Academy of Sciences of the United States of America. 2007. PMID 18056804. DOI 10.1073/pnas.0709487104.

    Cross-sectional study · 4,940 NHANES III and 5,473 NHANES 1999 to 2002 adults: with serum B12 above 148 pmol/L, homocysteine and MMA fell as folate rose; with lower B12, both metabolites rose as folate increased from about 20 nmol/L, suggesting a worsening of B12's enzymatic functions as folate status increases in B12-deficient people.

  17. 17.

    Odewole OA, Williamson RS, Zakai NA, et al.. Near-elimination of folate-deficiency anemia by mandatory folic acid fortification in older US adults: Reasons for Geographic and Racial Differences in Stroke study 2003-2007. American Journal of Clinical Nutrition. 2013. PMID 23945721. DOI 10.3945/ajcn.113.059683.

    Cross-sectional study · Random sample of 1,546 REGARDS participants aged 50 and over: median serum folate 34.2 nmol/L (15.1 ng/mL); 2 of 1,546 (0.1 percent) deficient below 6.6 nmol/L (3.0 ng/mL); folate-deficiency anemia in 1 of 1,546; 15.9 percent anemic overall.

  18. 18.

    Pfeiffer CM, Sternberg MR, Fazili Z, et al.. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. Journal of Nutrition. 2015. PMID 25733468. DOI 10.3945/jn.114.201210.

    Cross-sectional study · NHANES 2007 to 2008 (2,734 5-methylTHF and 2,707 UMFA samples): geometric mean 5-methylTHF 48.4 nmol/L in supplement users and 30.7 in non-users; UMFA detectable in more than 95 percent of both; UMFA above 1 nmol/L in 33.2 percent overall and 21.0 percent of fasting adults; concentrations differed by age and fasting time; associated with total folic acid intake, non-fasting, older age and higher red-cell folate.

  19. 19.

    Tsang BL, Devine OJ, Cordero AM, et al.. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. American Journal of Clinical Nutrition. 2015. PMID 25788000. DOI 10.3945/ajcn.114.099994.

    Systematic review and meta-analysis · 40 studies of women aged 12 to 49: by microbiologic assay, CC exceeded TT by 13 percent in serum or plasma folate and 16 percent in red-cell folate, with CT intermediate; protein-binding assays showed a larger serum difference (20 percent) and no consistent pattern in red cells.

  20. 20.

    Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA. 1995. PMID 7474275. DOI 10.1001/jama.1995.03530210052030.

    Cross-sectional study · Irish case-control data: NTD risk associated with early-pregnancy red-cell folate in a continuous dose-response relationship; 0.4 mg folic acid a day calculated to reduce NTDs by 48 percent; supplementation for high-risk women and fortification for the population are complementary.

  21. 21.

    Crider KS, Devine O, Hao L, et al.. Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ. 2014. PMID 25073783. DOI 10.1136/bmj.g4554.

    Prospective cohort · 247,831 participants in a Chinese community intervention and 1,194 in a randomized trial: 25.4 NTDs per 10,000 births at a red-cell folate of 500 nmol/L, 6 per 10,000 at 1,180 nmol/L; risk substantially attenuated above about 1,000 nmol/L; consistent with US prevalence before and after fortification.

  22. 22.

    MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991. PMID 1677062.

    Randomized trial · 1,817 women with a previous affected pregnancy randomized to folic acid, other vitamins, both or neither: 27 NTDs in 1,195 completed pregnancies, 6 in the folic acid groups and 21 in the others, a 72 percent protective effect (relative risk 0.28, 95 percent CI 0.12 to 0.71); other vitamins no significant effect.

  23. 23.

    Daly S, Mills JL, Molloy AM, et al.. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet. 1997. PMID 9400511. DOI 10.1016/S0140-6736(97)07247-4.

    Randomized trial · 121 women with red-cell folate 150 to 400 µg/L randomized to placebo or 100, 200 or 400 µg folic acid a day for 6 months: median increments 67, 130 and 200 µg/L and post-treatment medians 375, 475 and 571 µg/L; women above 400 µg/L have a very low NTD risk.

  24. 24.

    US Preventive Services Task Force; Barry MJ, Nicholson WK, Silverstein M, et al.. Folic Acid Supplementation to Prevent Neural Tube Defects: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA. 2023. PMID 37526713. DOI 10.1001/jama.2023.12876.

    Guideline · High certainty of substantial net benefit; all persons planning or able to become pregnant should take 0.4 to 0.8 mg of folic acid a day (A recommendation); about 3,000 US pregnancies affected by NTDs each year, many caused by low folate.

  25. 25.

    Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. American Journal of Clinical Nutrition. 2005. PMID 16210710. DOI 10.1093/ajcn/82.4.806.

    Systematic review and meta-analysis · 25 trials, 2,596 people, standardized to homocysteine 12 µmol/L and folate 12 nmol/L: 0.2, 0.4, 0.8, 2.0 and 5.0 mg folic acid a day lowered homocysteine 13, 20, 23, 23 and 25 percent; B12 (mean 0.4 mg) a further 7 percent; B6 no significant effect; 0.8 mg or more for the maximal effect, 0.2 and 0.4 mg giving 60 and 90 percent of it; larger effect with higher homocysteine or lower folate at baseline.

  26. 26.

    Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database of Systematic Reviews. 2017. PMID 28816346. DOI 10.1002/14651858.CD006612.pub5.

    Systematic review and meta-analysis · 15 trials, 71,422 people: myocardial infarction RR 1.02, death 1.01, stroke 0.90 (4.3 versus 5.1 percent), all high-quality evidence; about 143 treated for 5.4 years to prevent one stroke in the one mega-trial.

  27. 27.

    Huo Y, Li J, Qin X, et al.; CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015. PMID 25771069. DOI 10.1001/jama.2015.2274.

    Randomized trial · 20,702 adults with hypertension and no prior stroke or MI, median 4.5 years: enalapril plus 0.8 mg folic acid reduced first stroke from 3.4 to 2.7 percent (HR 0.79); MI 1.04, all-cause death 0.94; benefit consistent with low baseline folate.

  28. 28.

    Cole BF, Baron JA, Sandler RS, et al.; Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007. PMID 17551129. DOI 10.1001/jama.297.21.2351.

    Randomized trial · 1,021 people with a recent colorectal adenoma randomized to 1 mg folic acid a day or placebo: adenoma recurrence 44.1 versus 42.4 percent at 3 years (RR 1.04); among 607 with a second follow-up, advanced lesions 11.6 versus 6.9 percent (RR 1.67, p=0.05); higher risk of 3 or more adenomas and of non-colorectal cancers on folic acid.

  29. 29.

    Vollset SE, Clarke R, Lewington S, et al.; B-Vitamin Treatment Trialists' Collaboration. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals. Lancet. 2013. PMID 23352552. DOI 10.1016/S0140-6736(12)62001-7.

    Systematic review and meta-analysis · 13 trials, 49,621 participants, weighted average 5.2 years: folic acid quadrupled plasma folate (57.3 versus 13.5 nmol/L) with no significant effect on overall cancer (1,904 versus 1,809 cancers, RR 1.06, 95 percent CI 0.99 to 1.13) or any site; trial doses an order of magnitude above fortification.

  30. 30.

    Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. American Journal of Clinical Nutrition. 2007. PMID 17209196. DOI 10.1093/ajcn/85.1.193.

    Cross-sectional study · NHANES 1999 to 2002, 1,459 seniors: low B12 status (below 148 pmol/L or MMA above 210 nmol/L) carried odds of 2.7 for anemia and 2.5 for cognitive impairment; with low B12, serum folate above 59 nmol/L (80th percentile) carried odds 3.1 for anemia and 2.6 for cognitive impairment; with normal B12, high folate was protective against cognitive impairment (0.4); experimental investigation unethical.

  31. 31.

    Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. American Journal of Clinical Nutrition. 1997. PMID 9174474. DOI 10.1093/ajcn/65.6.1790.

    Laboratory method study · Acute feeding studies in young and elderly volunteers: unaltered folic acid appeared in serum at a threshold of 266 µg per meal from fortified cereal and bread, and above 200 µg from folic acid in saline, milk or bread; the chief risk of circulating folic acid is masking the diagnosis of cobalamin deficiency in pernicious anemia.

  32. 32.

    Troen AM, Mitchell B, Sorensen B, et al.. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. Journal of Nutrition. 2006. PMID 16365081. DOI 10.1093/jn/136.1.189.

    Cross-sectional study · 105 healthy postmenopausal women: unmetabolized folic acid detected in 78 percent of fasting plasma samples; NK cytotoxicity about 23 percent lower where it was detectable, stronger over age 60 and with higher concentrations.

  33. 33.

    Brouwer IA, van Dusseldorp M, West CE, et al.. Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. Journal of Nutrition. 1999. PMID 10356077. DOI 10.1093/jn/129.6.1135.

    Randomized trial · 66 healthy adults, 4-week controlled diets: a diet high in vegetables and citrus fruit (about 560 µg folate) and a low-folate diet (about 210 µg) plus 250 µg folic acid a day both improved folate status and lowered homocysteine; relative bioavailability of dietary folate 60 to 98 percent of folic acid.

  34. 34.

    Lamers Y, Prinz-Langenohl R, Brämswig S, Pietrzik K. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. American Journal of Clinical Nutrition. 2006. PMID 16825690. DOI 10.1093/ajcn/84.1.156.

    Randomized trial · 144 women aged 19 to 33 randomized to 400 µg folic acid, 416 µg [6S]-5-MTHF, 208 µg [6S]-5-MTHF or placebo for 24 weeks: red-cell folate rose more on 416 µg 5-MTHF than on folic acid or the lower dose (P less than 0.001); red-cell folate had not plateaued at 24 weeks while plasma folate plateaued after 12 weeks; preconception supplementation should exceed 4 weeks.

  35. 35.

    Halsted CH, Villanueva JA, Devlin AM, Chandler CJ. Metabolic interactions of alcohol and folate. Journal of Nutrition. 2002. PMID 12163694. DOI 10.1093/jn/132.8.2367S.

    Review · Folic acid absorption decreased in binge-drinking alcoholics and in volunteers fed alcohol with low-folate diets; monkeys fed alcohol 2 years lost hepatic folate stores with malabsorption and increased urinary loss; micropigs showed reduced intestinal reduced folate carrier; chronic alcohol impairs absorption, hepatic uptake and renal conservation of folate.

  36. 36.

    Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine. 2013. PMID 23288205. DOI 10.1038/gim.2012.165.

    Guideline · Meta-analyses have disproven the association between hyperhomocysteinemia and coronary heart disease and between MTHFR polymorphism status and venous thromboembolism; MTHFR polymorphism testing has minimal clinical utility and should not be ordered as part of a routine thrombophilia evaluation.

  37. 37.

    Jacob RA, Gretz DM, Taylor PC, et al.. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. Journal of Nutrition. 1998. PMID 9649607. DOI 10.1093/jn/128.7.1204.

    Laboratory method study · 8 women aged 49 to 63 in a metabolic unit fed 56 µg folate a day for 5 weeks then 111 µg for 4 weeks: subclinical deficiency with decreased plasma folate, raised homocysteine and urinary malondialdehyde, lymphocyte DNA hypomethylation and a raised dUTP/dTTP ratio; hypomethylation reversed with 286 to 516 µg a day, homocysteine only with 516.

  38. 38.

    Monneret D, Mestari F, Atlan G, et al.. Hemolysis indexes for biochemical tests and immunoassays on Roche analyzers: determination of allowable interference limits according to different calculation methods. Scandinavian Journal of Clinical and Laboratory Investigation. 2015. PMID 25608598. DOI 10.3109/00365513.2014.993691.

    Laboratory method study · Across 45 analytes, hemolysis raised concentrations of LDH, AST, folate, potassium, creatine kinase, phosphorus, iron and others in decreasing order; over 25 days, samples affected by more than 10 percent were under 5 percent for AST, folate and iron.

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