One in five women in the deficiency range? What folate does in the body and why supply often falls short

Folate is one of those vitamins people rarely think about until someone asks about their levels. In a Swiss study of 171 women of reproductive age, about one in five had red blood cell folate below the threshold regarded as deficiency, and more than nine in ten were below the benchmark the WHO names for protection in early pregnancy. This article explains what folate does in the body, how supply looks and what research on folic acid has shown so far.

Folate is needed wherever cells divide

Folate (vitamin B9) is the collective term for a group of related compounds. The body converts them into active folates that transfer small carbon units and are thereby involved in forming DNA building blocks and in cell division and growth. Together with vitamin B12, folate also plays a role in breaking down homocysteine, an intermediate of protein metabolism (EFSA 2023). Among other things, EFSA has recognised folate’s involvement in normal blood formation, cell division, homocysteine metabolism and normal function of the immune system (EFSA 2009).

This is especially visible in tissues that renew quickly. Red blood cells are the best-known example: if folate is lacking for a long time, precursor cells in the bone marrow cannot divide properly, and a particular form of anaemia develops, known as megaloblastic anaemia. It is the classic consequence of pronounced deficiency and occurs at much lower levels than those discussed for early pregnancy.

How supply looks in Switzerland

A cross-sectional study within the Swiss Iodine Survey 2015/16 measured red blood cell folate in 171 women of reproductive age. The average level was 442 nmol/L. 19.9 per cent of the women were below 340 nmol/L, the deficiency range, and 91.8 per cent below 906 nmol/L, the level above which the risk of neural tube defects falls markedly. Women who reported a folate-containing supplement (11 per cent) had higher levels on average than the rest (720 versus 420 nmol/L). The sample was a convenience sample and not representative, and this is an observation, not an intervention study (Herter-Aeberli 2020).

Diet does not close this gap on its own, for several reasons. The D-A-CH countries give 300 µg dietary folate equivalents (DFE) per day for adults, EFSA 330 µg. Folate is sensitive to light, oxygen and heat, and the Swiss Society for Nutrition assumes an average loss of 35 per cent during preparation. A plate of spinach provides a little over 100 µg raw and correspondingly less once cooked. There is no obligation to fortify foods with folic acid in Switzerland or in the EU countries. In the same survey only 2 per cent of participants knew which foods contain folate, although 74 per cent could name at least one source (Herter-Aeberli 2020).

Food	Folate per 100 g	Folate per portion
Endive	109 µg	131 µg (120 g)
Spinach	94 µg	113 µg (120 g)
Chickpeas, cooked	68 µg	102 µg (150 g)
Cauliflower	56 µg	67 µg (120 g)
Walnuts	112 µg	28 µg (25 g)
Egg, hard-boiled	60 µg	33 µg (1 egg)

The values come from the Swiss food composition database and are approximate. Most folate is retained when vegetables are eaten raw or cooked only briefly and gently.

Folate, folic acid, 5-MTHF: three forms with different properties

In everyday speech the terms are often equated. Folate occurs naturally in food. Folic acid is the synthetic, very stable form added to food supplements and fortified foods. A third form found in supplements is 5-methyltetrahydrofolate (5-MTHF), the predominant active form in blood; it is authorised in the EU as a nutrient source. Because folic acid is used more efficiently than food folate, nutrition societies calculate in folate equivalents: 1 µg DFE equals 1 µg food folate, but only 0.6 µg folic acid from fortified foods or taken with a meal.

Whether 5-MTHF is superior to folic acid is not conclusively settled. In a randomised trial with 144 women, red blood cell folate rose more with 5-MTHF than with 400 µg folic acid (Lamers 2006). A small crossover study with 24 women showed something similar for plasma folate, regardless of the common MTHFR gene variant 677C→T (Prinz-Langenohl 2009). Both are blood values, not health endpoints; the Cochrane authors describe 5-MTHF merely as a proposed alternative.

Homocysteine responds to folic acid, especially together with vitamin B12

A meta-analysis of 25 randomised trials with 2,596 people showed that blood homocysteine fell by about 20 per cent with 0.4 mg folic acid daily and by about 23 per cent with 0.8 mg. Vitamin B12 lowered it by a further 7 per cent or so; vitamin B6 had no significant influence (Homocysteine Lowering Trialists’ Collaboration 2005). This is a laboratory value; whether it translates into clinical changes is not answered by the work. Accordingly, some combinations pair European plant extracts with micronutrients such as folic acid, vitamin B6 and vitamin B12.

Pregnancy is the best-documented chapter

Around day 28 after conception the neural tube, the precursor of the brain and spinal cord, closes, at a time when many women do not yet know they are pregnant. Two trials in the early 1990s prompted today’s recommendations. In the British Medical Research Council vitamin trial, 1,817 women who had already had a child with a neural tube defect received folic acid, other vitamins, both or nothing: the folic acid groups had 6 new cases, the others 21 (randomised trial, MRC 1991). At 4 mg daily, the dose was about ten times today’s standard recommendation, and these were women at high baseline risk. In Hungary, among women without a previous case, no neural tube defect occurred with a multivitamin containing folic acid, compared with six in the comparison group (randomised trial, Czeizel 1992); because a multivitamin was tested, this cannot be attributed to folic acid alone.

A Cochrane review in 2015 pooled five such trials with around 6,700 participants: the relative risk was 0.31 with folic acid; for other malformations the data were insufficient for a conclusion (De-Regil 2015). Red blood cells live around 120 days, so their folate level responds only slowly to a change in intake (EFSA 2023). A modelling study using data from two Chinese population studies found about 25 neural tube defects per 10,000 births at 500 nmol/L and about 6 at 1,180 nmol/L; the WHO gives 906 nmol/L as the threshold (Crider 2014). Accordingly, the recommendations start early:

Source	Recommendation
D-A-CH	In addition to diet, 400 µg synthetic folic acid daily, from at least four weeks before pregnancy to the end of the first trimester
Switzerland (FOPH, Federal Nutrition Commission)	1996 recommendation: 0.4 mg folic acid daily in tablet form
USPSTF (USA, 2023)	0.4 to 0.8 mg daily, from at least one month before conception into the first two to three months of pregnancy

Safety and use: what to consider regarding upper limits, vitamin B12 and medicines

In 2023 EFSA confirmed the upper limit for folic acid from supplements and fortified foods at 1,000 µg daily for adults, including pregnant and breastfeeding women. For adolescents aged 15 to 17 the limit is 800 µg, for children aged 11 to 14 it is 600 µg, 7 to 10 years 400 µg, 4 to 6 years 300 µg and 1 to 3 years 200 µg. The limit also applies to the authorised 5-MTHF salts.

The reason is not a direct side effect of the vitamin but another concern: in vitamin B12 deficiency, folic acid can correct the anaemia without addressing the neurological consequences of the deficiency, which could then progress unnoticed. In known or suspected B12 deficiency, intake should therefore be medically supervised. EFSA found insufficient evidence for a causal link between high folate intake and impaired cognition or colorectal and prostate cancer. Whether unmetabolised folic acid in the blood is health-relevant is considered open (EFSA 2023).

Folate antagonists such as methotrexate and some antiepileptics, for example carbamazepine or valproic acid, interfere with folate metabolism. The USPSTF recommendation explicitly does not apply to people taking such medicines, nor to women with a previous affected pregnancy; medical advice is needed here. The stated serving of supplements should not be exceeded.

Conclusion: the role of folate is well documented, the supply situation deserves attention

What has been shown is that folate is involved in blood formation, cell division and homocysteine metabolism, that folic acid lowers homocysteine, and that fewer neural tube defects occurred with folic acid when preparing for pregnancy. A Swiss observation suggests that supply in many women of reproductive age is below the benchmarks; it comes, however, from a small, non-representative sample. What remains open is which dose suits the individual case (the USPSTF gives 0.4 to 0.8 mg, the MRC trial tested only 4 mg), whether 5-MTHF is equivalent to folic acid, how genetic variants weigh in and what high intakes mean in the long term.

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This article provides general information about folate and folic acid and does not replace medical advice, diagnosis or treatment. If you have health concerns, please consult a doctor or pharmacist.

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Sources

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• De-Regil LM et al.: Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2015;(12):CD007950. Systematic review. PMID 26662928
• Crider KS et al.: Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ 2014;349:g4554. Modelling study. PMID 25073783
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• Homocysteine Lowering Trialists’ Collaboration: Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 2005;82(4):806–812. Meta-analysis. LSHTM
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