Key points
What folate is and what forms it takes
Folate (vitamin B9) is needed to make DNA — the cell’s genetic material — and to neutralize homocysteine, so it matters for the blood, the mucous membranes and the nervous system of the unborn baby (Burgerstein, Handbuch Nährstoffe 2015, p. 70–71). Cooking destroys 50–90% of folate (Burgerstein, Handbuch Nährstoffe 2015, p. 72).
Folate means the natural forms of B9 in food; folic acid is the synthetic form used in supplements and to fortify flour; methylfolate (5-methyltetrahydrofolate) is the ready-to-use active form that the cell obtains with the help of the MTHFR enzyme. Without vitamin B12, folate cannot work properly (Burgerstein, Handbuch Nährstoffe 2015, p. 74).
Pregnancy: the best-proven effect
What an “MTHFR mutation” means
C677T is a common variant of the gene: two copies of it (the TT genotype) are carried by 1% or fewer to 20% or more of people in different populations. Mothers with TT had roughly twice the odds of spina bifida in their baby (odds ratio 2.0), and, according to some data, this risk depends on folate status (Botto LD Am J Epidemiol 2000. PMID 10791559[5]).
An MTHFR test is not needed in routine evaluation for a tendency to thrombosis: the American College of Medical Genetics and Genomics (ACMG) considers its clinical utility minimal (Hickey SE Genet Med 2013. PMID 23288205[9]).
Methylfolate: what is known about it
In a randomized study (144 women, 24 weeks), 416 µg of methylfolate raised red blood cell folate more than 400 µg of folic acid did; the authors call it a possible alternative (Lamers Y Am J Clin Nutr 2006. PMID 16825690[7]).
But that is a blood level, not the number of defects: protection against defects was shown for folic acid (De-Regil LM Cochrane Database Syst Rev 2015. PMID 26662928[3]). The genotype does not make methylfolate mandatory, and the upper limit applies to it too (EFSA NDA Panel EFSA J 2023. PMID 37965303[8]).
Folate and homocysteine
In a meta-analysis of 25 trials, with baseline homocysteine of 12 µmol/L (U.S. lab reports use the same unit) and folate of 12 nmol/L (5.3 ng/mL), 0.4 mg of folic acid a day lowered homocysteine by 20%, and 0.8 mg by 23%. B12 gave another 7%; no significant effect of B6 was shown (Homocysteine Lowering Trialists' Collaboration Am J Clin Nutr 2005. PMID 16210710[10]), although the handbook suggests it as well (Burgerstein, Handbuch Nährstoffe 2015, p. 77–78).
Why more is not better
The handbook calls folic acid non-toxic even at high doses and gives the authors’ own doses, many times above the current limit (Burgerstein, Handbuch Nährstoffe 2015, p. 72–73). Current guidelines are more cautious. The European Food Safety Authority (EFSA) kept the upper limit at 1000 µg a day for adults, including pregnant and breastfeeding women — for folic acid and methylfolate from supplements and fortified foods (not for folate from ordinary food); at 15–17 years it is 800 µg. The key risk is with B12 deficiency: folic acid can clear up the anemia while nerve damage may progress (EFSA NDA Panel EFSA J 2023. PMID 37965303[8]); the handbook warns about the same thing (Burgerstein, Handbuch Nährstoffe 2015, p. 73). More in the article on B12 deficiency.
What the studies showed
| What was tested | Who took part | Result |
|---|---|---|
| Folic acid 4 mg after a previous pregnancy with a defect, 1991 | 1817 high-risk women, outcome known in 1195 | Defects: 6 cases vs 21, 72% protection |
| Multivitamins with 0.8 mg folic acid, Hungary (2011 review) | Women planning a pregnancy | 93% fewer first-occurrence cases (according to the author); in the Cochrane review no significant effect was shown for first occurrences |
| Cochrane review, 2015 | 5 trials, 7391 women | Lower risk of neural tube defects, relative risk 0.31 |
| MTHFR genotype and folic acid, 2011 | 932 women with known genotype | TT: lower folate, but the link with dose did not depend significantly on genotype |
| Folic acid doses and homocysteine, 2005 | 25 trials, 2596 people | 0.4 mg: −20%; 0.8 mg: −23%; 5 mg: −25% |
| Methylfolate vs folic acid, 2006 | 144 women, 24 weeks | Red blood cell folate rose more on 416 µg of methylfolate |
Not everything is equally proven: for cleft palate and lip, heart defects and miscarriage, folic acid in the Cochrane review showed neither benefit nor harm (De-Regil LM Cochrane Database Syst Rev 2015. PMID 26662928[3]); EFSA considered the link between excess folate and colorectal cancer, prostate cancer and cognitive decline with low B12 unproven (EFSA NDA Panel EFSA J 2023. PMID 37965303[8]).
Who should be more careful
- If you have already had a pregnancy affected by a neural tube defect, the dose is set by a doctor: in the UK Medical Research Council (MRC) trial it was 4 mg a day — above the upper limit (Czeizel AE Ann Nutr Metab 2011. PMID 21865678[2]).
- If you have numbness, tingling, unsteady gait or anemia, check B12 first.
- If you take several supplements, add up the folic acid and methylfolate from all of them: the limit of 1000 µg a day for adults (800 µg at 15–17 years) applies to their total from supplements and fortified foods, but not to folate from ordinary food (EFSA NDA Panel EFSA J 2023. PMID 37965303[8]).
Bottom line
Folic acid before conception is one of the best-proven supplements: 400–800 µg a day lowers the risk of neural tube defects in the baby. The MTHFR variant is common and does not rule it out; methylfolate is a possible alternative, but not a required replacement. It is not worth taking more than 1000 µg a day from supplements without a doctor’s prescription. You can choose the form and dose when planning a pregnancy at a consultation.
This material is for information only and does not replace a doctor’s consultation. The form and dose of folate are chosen by a doctor based on your medical history and test results.
References
- MRC Vitamin Study Lancet 1991. PMID 1677062
- Czeizel AE Ann Nutr Metab 2011. PMID 21865678
- De-Regil LM Cochrane Database Syst Rev 2015. PMID 26662928
- USPSTF JAMA 2023. PMID 37526713
- Botto LD Am J Epidemiol 2000. PMID 10791559
- Crider KS Am J Clin Nutr 2011. PMID 21508090
- Lamers Y Am J Clin Nutr 2006. PMID 16825690
- EFSA NDA Panel EFSA J 2023. PMID 37965303
- Hickey SE Genet Med 2013. PMID 23288205
- Homocysteine Lowering Trialists' Collaboration Am J Clin Nutr 2005. PMID 16210710
Key facts
- In 1817 women who had already had a pregnancy affected by a neural tube defect, folic acid before conception at 4 mg a day lowered the risk of recurrence by 72% (MRC Vitamin Study, Lancet 1991; Czeizel AE, Ann Nutr Metab 2011).
- Cochrane review (5 trials, 7391 women): daily folic acid lowers the risk of neural tube defects, relative risk 0.31, high-quality evidence (De-Regil LM, Cochrane Database Syst Rev 2015).
- The U.S. Preventive Services Task Force recommends 400–800 µg of folic acid a day for everyone who is planning a pregnancy or could become pregnant (USPSTF, JAMA 2023).
- Two copies of the C677T variant of the MTHFR gene (for the enzyme methylenetetrahydrofolate reductase) are carried by 1% or fewer to 20% or more of people in different populations (Botto LD, Am J Epidemiol 2000); the link between blood folate and folic acid dose did not depend significantly on genotype (Crider KS, Am J Clin Nutr 2011).
- The upper limit for adults, including pregnant women, is 1000 µg a day of folic acid and methylfolate from supplements and fortified foods (not folate from ordinary food); the main risk of excess is linked to B12 deficiency (EFSA, EFSA J 2023).
