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The benefits and risks of folic acid supplementation

Could a vitamin with proven benefits in one group cause harm to another? That’s the growing concern with folic acid, the vitamin that dramatically reduces the risk of neural tube birth defects such a spina bifida. Studies designed to explore the possible benefits of folic acid for heart disease, stroke and cancer are giving out some worrying signs: At best, folic acid is ineffective, and at worst it may be increasing the risks of some cancers. So what does this say about routine supplementation for the typical healthy individual, and its overall risk and benefit?

Folate (vitamin B9) is an essential nutrient found green, leafy vegetables, broccoli, peas, corn, oranges, grains, cereals, and meats. Folate has important roles in the synthesis of DNA, and consequently cell division. Significant folate deficiency can lead to macrocytic anemia. Folic acid, a synthetic form of folate, is used in multivitamins supplements because it is better absorbed.

Folic acid’s benefits in pregnancy are well documented. Supplementation before conception, and in the first few weeks of pregnancy, significantly and substantially lower the risk of several different birth defects, including neural tube defects (NTDs). The neural tube is the embryonic precursor to the brain and spinal column. NTDs include very serious defects like spinal bifida and anencephaly, birth without part of the brain.

The stakes are high, and because the neural tube forms so early in pregnancy (day 26 to 28), deficiencies must be corrected before a woman knows she is pregnant. This has led to public health strategies that mandate supplementation in food products: In both the United States and Canada, folic acid has been added to white flour since the late 1990’s, where it finds its way into baked goods like bread. Following food fortification, neural tube defects have subsequently dropped.

In addition to food fortification, women that could become pregnant are generally advised to take a multivitamin containing at least 0.4mg of folic acid daily. Women at high risk of NTDs may be advised to take higher doses. But as higher doses of folic acid can mask the symptoms of Vitamin B12 deficiency, higher doses warrant medical advice and supervision.

Even with fortification, it’s clear there are still opportunities to improve folic acid consumption in pregnancy. A Canadian population study showed that 20% of women of childbearing age failed to have appropriate folic acid levels in their blood. And while virtually no-one was dangerously deficient, over 40% had levels that would be considered high.

Beyond pregnancy

Observational trials have correlated a diet rich in fruits and vegetables with a lower risk of diseases like colorectal cancer. Based on this epidemiologic evidence, several randomized controlled trials were initiated investigating the effect of the B vitamins (including folic acid) on cancer risk. Folic acid held particular promise because of its proven effects preventing neural tube birth defects.

But the effects were not as expected.

The Warning Signals

That folic acid may interfere with cancer has been known since the 1940’s. The chemotherapy drug methotrexate is an antifolate agent that blocks the metabolism of folic acid, developed after it was noted that a diet deficient in folic acid helped patients with leukemia.

Studies of folic acid supplementation are raising flags about the potential risks of therapy, possibly as a result of excessive consumption. One of the most startling was a study that looked at folic acid supplementation in patients with colorectal adenomas, which are cancer precursors. Participants were randomized to folic acid 1mg or placebo for up to six years. While it was hypothesized that folic acid would provide a protective effect, the results were disappointing. Not only did folic acid have no effect on adenoma incidence (even in those with low folate status),  there was a significant increase in the risk of non-colorectal cancers (10.5% vs. 6.3%), due mainly to an excess of prostate cancers.

Futher worrying evidence emerged in 2009, when a Norwegian study of heart failure patients was published. Researchers randomized almost 7000 patients to folic acid and vitamin B12 versus other vitamins or placebo. The vitamins significantly raised the risks of both cancer and all-cause mortality, driven mainly by more cases of lung cancer. On balance, looking at heart disease, folic acid supplementation don’t seem to have any persuasive effects, either. In combination with other B-vitamins to lower homocysteine levels it hasn’t been shown to have meaningful effects on cardiovascular disease prevention, either.

The same worrying cancer signal has appeared with breast cancer in postmenopausal women, even while dietary folate seems to be beneficial. And in studies looking at prostate cancer, when folic acid is combined with other vitamins, the data are unclear.

So could fortification be causing harm? While correlations have been drawn between food fortification and population studies of colorectal cancer, causality hasn’t been established. Screening rates or other factors could be contributing. Still, the idea is troubling, even though the harms (if real) are slight compared to the demonstrable and significant benefits fortification has played  in reducing NTDs.

Conclusion

In women of childbearing age, folic acid supplementation has a demonstrable and meaningful benefit, reducing the incidence of NTDs. Its use in this population is evidence-based and demonstrably effective. And for treatments for conditions like end-stage kidney disease, folic acid may be of benefit. But when we look at the use of folic acid for primary prevention, the data are less clear. In children, men, and women beyond their childbearing years, supplementation in the absence of deficiency has no demonstrated health benefits, and there are worrying signals that it may raise cancer risks, possibly by “feeding” existing cancers.

Is fortification of our food supply harming and hurting? The benefits on NTD incidence have been demonstrated, while the harms haven’t been proven yet. Still, folic acid’s evolving story may become a cautionary tale about the consequences of fortification and supplementation with the hope of improved health outcomes. If we’re not in our childbearing years, we may be better off relying only on food sources for folate. So pass the spinach, and hold the multivitamins with folic acid.

Posted in: Clinical Trials, Epidemiology

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30 thoughts on “The benefits and risks of folic acid supplementation

  1. passionlessDrone says:

    Hello friends –

    Even in pregnancy, our target of neural tube formation happens very early, and women are recommended they continue taking folic acid through term; up and above whatever they happen to be eating which has been supplemented. While we have no doubt tackled NTDs, I’m not convinced we understand well enough what else we might be doing.

    Even today, we really don’t understand exactly how folic acid exerts its protective effect on NTDs, but epigenetic manipulation is suspected. I think its very unlikely that we would find that the one and only effect of folic acid during fetal development is the one we’d like it to have.

    http://www.ncbi.nlm.nih.gov/pubmed/19924280

    Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use.

    - pD

  2. Angora Rabbit says:

    This is a terrific post, Scott. Thank you very much for a nice summary of this complex issue. You made me smile because this very question is on the final exam that my nutrition grad students just took (and which I’m about to grade).

    I could add to your excellent points two additional thoughts? The first is that the folate supplementation has not reduced North American rates of neural tube defects as much as had been proposed prior to supplementation. The prediction was ~50% reduction (3000 cases/yr) and the numbers are coming out ~30% (I haven’t looked to see which link you’re using, so our numbers might differ a bit). Part of this is because folate deficiency isn’t the only risk factor for NTDs. The failure to elevate folate in certain populations is also clearly a piece of this. In addition, the retrospectroscope (one of my favorite research tools) revealed that North American populations weren’t as deficient as those populations (e.g. China) where the NTD reduction was quite dramatic. Still, NTDs and anencephaly are horrible conditions, and so there is an ethical issue (if the cancer findings are true) about how do we balance these competing interests between a small number of something dreadful and a possible large number of increased tumor growths.

    My other thought is about vitamin B12 status. A major concern during the development of the folate supplement policy was (and remains) the potential for folate to mask B12 deficiency, known as the “folate trap.” This tends not to be a problem for women of child-bearing years, but it may be a significant concern for the elderly, especially now with their high intake of folate-fortified flours/foods and their reduced ability to absorb dietary B12, thus increasing their risk for pernicious anemia and possibly neurological problems. There is an active conversation whether B12 should have been supplemented with the folate.

    No easy answers, and hopefully good research in the future will help to resolve this conundrum.

  3. Scott says:

    pD’s got a very interesting point. Is there any established value to continuing supplementation after the early stage of pregnancy?

  4. daedalus2u says:

    Neural tube defects are partially mediated through nitric oxide. Nitric oxide synthase inhibitors cause neural tube defects and these are rescued by folate. NO donors cause neural tube defects and these are rescued by folate. Thalidomide is a nitric oxide synthase inhibitor and causes neural tube defects (among other things).

    Valproate causes neural tube defects and also interferes with vascular tube formation. The interference of vascular tube formation by valproate is potentiated by NOS inhibitors and rescued by NO donors.

    http://molpharm.aspetjournals.org/content/65/3/520.long

    Smoking causes a slight reduction in neural tube defects. I suspect this is due to cross talk of carbon monoxide with NO signaling.

    To answer Scott, that is unknown and probably unknowable at the present state of knowledge. Folate acts as a methyl donor, and methylation of DNA is extremely important in the proliferation and differentiation that is going on during development. What you want is the right amount. What that right amount is, is probably idiosyncratic and would depend on the specifics of the genotype of the fetus and the levels of other nutrients, but also what phenotype you want that genotype to produce.

    The reason that cells in the body are different is because they have differentiated and so different parts of the genome have been silenced. Much of that silencing is done by DNA methylation. No doubt folate is important in that, but how much, where, when and for how long and for which types of cells is a complex question without a simple answer.

  5. Angora Rabbit says:

    @Scott: Is there any established value to continuing supplementation after the early stage of pregnancy?

    That’s a good question. The suggestion is to give folate as a supplement. But there’s a problem with that. The neural tube forms before most pregnancies are recognized. By the time the woman sees her physician (and gets her perinatal vitamins and minerals), the critical window for NTD has often passed. Hence there needs to be a way to get folate into women of child-bearing years prior to pregnancy recognition. That’s a major reason why the decision was to fortify a common food stuff, as opposed to relying on a perinatal supplement.

    March of Dimes ran a major publicity campaign when fortification was introduced to get women to increase their intake of foods that are good folate sources (like legumes). Unfortunately the women’s behaviors just didn’t change as much as was hoped and so fortification is still the preferred intervention right now.

  6. Anthro says:

    How many times must it be said. Eat your veggies, including leafy greens, as a large part of a balanced diet. Why is that so hard for so many? I have lots of easy recipes for those who say ‘ick”.

    Just think of the effect on birth defects if we marketed veggies the way we market sugary cereal to children.

  7. Aw crap. We take yer basic water-solubles as a supplement — B-complex + C — because we’re depressives, and it’s one way to avoid the depression & irritability > bad eating > low B6 > depression and irritabilty cycle. We’re also mostly vegetarian, and while I think our B12 is probably fine I like to know that it’s definitely fine.

    But if the folate in there is bad for us (my beloved smokes about 5 cigars a week, compounded by type 2 diabetes) now I have to make life more complicated and buy B6 and B12 individually.

    Crap.

    (Yes, we eat lots of fruits and veggies. Except when my beloved is cooking.)

  8. Harriet Hall says:

    Folate supplementation is recommended for patients who take methotrexate for rheumatoid arthritis. What are your thoughts about that use?

  9. One of the other congenital malformations that folic acid prevents is cleft lip & palate (I believe it’s said to lower cases 20 to 25 percent). Which is not as gnarly as spinal bifida can be, but still worth preventing.

    My understanding is that with cleft lip & palate, the risk is partly based on ethnicity. Native Americans having the highest rate of CLCP followed Asians, Europeans, then African. I believe this is regardless of current location (so African Americans have lower risk of CLCP than Asian Americans).

    I only point this out because I was curious when Angora Rabbit pointed out that North America populations were less inclined toward folate deficiency than China populations. Is it known if this is entirely due to diet, supplementation differences or could there be differences in absorption or processing of folate between European (descent) and Asians?

  10. Josie says:

    So, from all the research and commentary from “nutritionally authoritative” sources I’ve seen, vitamins make really expensive pee.

    This is the consensus I saw daily even when I was working in the Type II Diabetes/Obesity world and kept up with that literature.

    What then is the deal with pre-natal vitamins? For years now I have shunned supplements and focused on eating a healthful diet…if I get pregnant I need to abandon that and go with the better-living-through-a-pill approach?

    I am really curious if these vitamins are actually uber-beneficial or if they are sort of a standard care cover-all-bases sort of thing.

    Also…
    Anyone else remember the Daisy Fuentes ads in the subway about how “Daisy isn’t pregnant now but someday she will be…so she takes folic acid supplements) –from the 90′s.

  11. Scott says:

    The suggestion is to give folate as a supplement. But there’s a problem with that. The neural tube forms before most pregnancies are recognized. By the time the woman sees her physician (and gets her perinatal vitamins and minerals), the critical window for NTD has often passed. Hence there needs to be a way to get folate into women of child-bearing years prior to pregnancy recognition.

    For planned pregnancies, it’s relatively easy – start the supplement prior to starting trying to get pregnant.

    Harder for unplanned, of course. Just one of the things which makes such questions hard…

  12. tanha says:

    Scott, can you please comment on these two issues:

    Deplin (15 mg “methylated” folate marketed for depression)

    Reproductive Endocrinologists testing for MTHFR mutations for patients with recurrent pregnancy loss — then recommending Deplin or high dose OTC folic acid during pregnancy.

  13. tanha says:

    “What is the deal with prenatal vitamins?”

    @Josie I don’t know what “nutritionally authoritative” sources you have “researched” but the AAFP recommends pregnant women supplement with .4-.8 mg folic acid to prevent NTD. Many pregnant women are too nauseous during their first trimester to consume adequate nutrition through their diet and fortunately for them they have prenatal vitamins to prevent nutrient deficiencies (namely folic acid). It’s an option you can consider for your future pregnancy.

    http://www.aafp.org/afp/2005/0401/p1307.html

  14. Jeff says:

    Folate studies have certainly gotten conflicting results. The post refers to a 2006 meta-analysis which found that folic acid supplementation did not reduce the risk of cardiovascular disease in those with a prior history of vascular disease. In 2007 the Lancet published a meta-analysis which concluded that supplementation does reduce the risk of stroke:
    http://www.ncbi.nlm.nih.gov/pubmed/17544768

    At least one epidemiological study found that folic acid supplementation reduced the risk of breast cancer:
    http://www.ajcn.org/content/89/2/624.abstract

  15. CLK says:

    Crap.
    So I was diagnosed through blood work with MTHFR gene deficiency, 2 bad copies actually and placed on a methylated folate, B6 and B12 supplement. I do have a history of B12 deficiency when I tried to be a vegan in my early 20′s (because, you know I started with diet woo to try and get better before moving on to other kinds of woo) and there is a family history of NTD.
    It correlated with an improvement in my level of fatigue, though I haven’t been taking it long enough to know if there is a relationship there.
    My doctor seems to think that my low tolerance of medications in general, and a disproportionate number of adverse drug reactions is related to being a “poor methylator”. This gene deficinecy is apparently part of that problem.
    I have been able to find little to no info on this except as it relates to pregnancy though. And increased risk of cancer seems like it would make this supplementation potentially dangerous.

  16. hokie98 says:

    That’s for the post. I read something similar a couple of years ago in a parenting mag (maybe Parenting..) about a couple of young mothers who were diagnosed with colon or lung cancer and wondered if taking excessive amounts of folic acid was to blame. Most had been on prenatal vitamins (with .8mg) for years – while pregnant, nursing, and in between pregnancies. That article always stuck in the back of my mind.

    I’m 6 months pregnant with my second child. It’s very hard to find a prenatal vitamin that doesn’t have at least .8 – 1 mg of folic acid. I took .4mg prior to becoming pregnant for several months (my OB said .4mg was sufficient), and took .4mg throughout the first trimester. These days I’m only taking a fish oil supplement, but no vitamins. I do eat a varied, healthy diet. But I can’t help but to think of all of the other childbearing age women that I know that take prenatals just as a multipurpose vitamin while NOT pregnant or trying to conceive, and wonder if it will have an adverse affect. Not to mention I think of the probably close to 2 yrs where I took prenatals – prior to conception of my first child, during the pregnancy and for a while afterwards. I’ve had several OB/Gyns tell me that it’s perfectly safe to take prenatals, even when not pregnant, but given such information as this, I do wonder….

    By the way, I think it’s worth mentioning that you if wish to reduce the amount of folic acid you consume through fortification, try to steer clear of processed flours. It’s hard to find white flour that isn’t ‘enriched’, but whole wheat flours contains naturally occurring folate and is NOT enriched (unless otherwise mentioned). On the flip side, looking in my pantry, looks like even whole wheat pasta is enriched. However, crackers, etc. made with whole wheat seems to NOT be enriched.

  17. LMA says:

    OOooh, yes, yes, yes, Harriet; you asked my exact question … I’m also awaiting a reply as this concerns me personally.

    1. Scott Gavura says:

      @Harriet @biopunk @LMA:
      I restricted my focus to primary prevention and didn’t look at situations where there’s a therapeutic rationale for folic acid supplementation. However, my understanding of the situation you describe is that folic acid may reduce the acute toxicity of methotrexate (MTX) without compromising its efficacy. (Ref) This is a situation where there are therapeutic benefits, which would mean a different risk-benefit perspective than in a primary prevention situation. I don’t think there are enough data to estimate a number needed to treat (NNT), or number needed to harm (NNH), but I suspect that the benefits probably dominate under this clinical circumstance, especially when MTX doses can be maintained. Perhaps a rheumatologist or other subject matter expert can add their perspective.

  18. biopunk says:

    I’m with Harriet and LMA: 6 years of 2mg folic acid supplementation.

    Add me to the list of the “concerned”…

  19. Angora Rabbit says:

    It may be helpful to consider, as we think about folate supplementation, that no one is saying that folate is a carcinogen. Far, far from it. It does not and cannot cause cancer. A better albeit inexact parallel in understanding what is happening is the relationship between increased screening and the increased diagnosis of breast and prostate cancer. When screening increased, diagnosis increased simply because detection had improved; once those cases were caught, rates of breast and prostate cancer flattened out again.

    For folate, what is happening is that, for a growth that already exists and when folate is already marginal, the increased folate intake provides greater opportunities for the cells to grow. (Folate is needed for DNA synthesis.) Current understanding is that we are seeing that sort of population blip (if indeed the blip is real, which is arguable), and that as folate intakes stabilize the increased tumor / growth incidence will disappear.

    Let’s put it another way – I’m not stopping my folate supplementation. :)

    Thanks MicheleinMichigan for pointing out midfacial clefting as well, another defect linked to inadequate folate.

  20. vicki says:

    Angora Rabbit:

    If you’re saying “folate doesn’t cause cancer, it just makes tumors that are already there grow faster,” I don’t find this comforting. You mentioned prostate cancer: historically, that’s one that men tend to die with rather than of, because it’s slow-growing. Speeding the growth of those tumors could do real harm.

    So could speeding the growth of other tumors, including some that are found in women who are taking prenatal vitamins. (That’s aside from the folate in the morning bagel, the lunchtime sandwich, or a slice of cake for dessert.)

    I’m not particularly worried personally, but that’s because I have never sought to become pregnant (and in fact take precautions so I won’t) and therefore don’t take those vitamin pills. That doesn’t mean it isn’t a real issue, including for women I know and care about.

    The population of people taking prenatal vitamins will have little or no overlap with those at risk for prostate cancer (though there may be households where a man has decided it’s simpler to take the same vitamins as his female partner, rather than buy two kinds of vitamin pills), but

  21. Josie says:

    “Many pregnant women are too nauseated during their first trimester to consume adequate nutrition through their diet and fortunately for them they have prenatal vitamins to prevent nutrient deficiencies”

    ding!

    That is what I was looking for.

    As for my nutritionally authoritative sources, before my current research focus in pancreatic cell therapies, I worked in type II diabetes and obesity. The research institute I worked at is focused on nutrition and lifestyle diseases. As part of the research community we had weekly seminars with invited speakers on a variety of topics –including current research on efficacy of various supplements. There were also journal articles that made my reading list even though they didn’t deal specifically with my little receptor of interest at the time.

    That’s all I meant –scientific literature as opposed to the part-time GNC store clerk :)

  22. Artour says:

    > Could a vitamin with proven benefits in one group cause harm to another?

    In my experience, YES. It relates to many situations and substances.

    I teach medical breathing retraining techniques practiced by 100′s of doctors in Russia. They found that the effects of many substances depend on automatic breathing patterns.

    For example, if antibacterial soaps do a good job for ordinary people, when my student increase their body oxygen levels (by slowing down or normalizing their breathing), the same soap creates irritation and cracking of hands.

    If they like coffee and it helps them to function better, then after breathing retraining (usually some 3-5 weeks), the same coffee causes heart palpitations and makes them jittery and anxious. So, they quit is themselves.

    The effect is probably linked with cellular CO2 and O2 content, because most modern people are hyperventilators (search for Hyperventilation Prevalence Medical Research). Low alveolar CO2 (hypocapnia) causes low O2 (tissue hypoxia) due to CO2-vasodilation and the suppressed Bohr effect.

  23. Roger Kulp says:

    So what does this say about routine supplementation for the typical healthy individual, and its overall risk and benefit?

    Like anything else,if you are healthy enough not to need it,you shouldn’t bother taking it.Too many people taking something and not needing it,and therefore getting no benefit,only help to drive people who really need something away from taking it.

    Aside from neural tube defects,there are MTHFR mutations,and other defects in folate metabolism,and cobalamin transport. Something that researchers have linked to not only neural tube defects,but autism spectrum disorders,most notably Jill James of Arkansas Children’s Hospital Metabolic Genomics Laboratory,who published her first landmark study on this,in 2004.
    http://www.jpands.org/vol9no4/boris.pdf

    She has published a lot more since.It has been twisted to some degree by the antivax crowd,but not to the extent mitochondrial dysfunction has,because it is a rarer condition needing more specialized tests.

    Not only do the children have problems in this area,but the mothers usually do too.Megaloblastic anemia,heart problems, cerebrovascular disease,and more.Often starting in childhood. The anemia is a major cause of GI disease,and failure to thrive/grow in these children,and can be the first sign of the disease.The families often have a history of stillbirth and neural tube defects.In more serious cases,like mine,there are not only MTHFR and folate issues,often with two or more genes,but also organic acidemias,involving methylmalonic acid and homocysteine.

    http://genoma.ib.usp.br/wordpress/publicacoes/publicacoes/2008-nogueira-kok.pdf

    If the mother has MTHFR mutations,or in our case,multiple polymorphisms on each of more than one gene,you can take all of the OTC folic acid you want,but it won’t do any good,you need to take the more specialized folinic acid form.There is a call for B12 deficiency to be added to Expanded Newborn Screening
    http://jama.ama-assn.org/content/305/12/1198.extract

    ,but there needs to be more testing of mothers for defects of folate metabolism and cobalamin transport.

  24. GinaPera says:

    Thank you for this important post.

    I am trying to recall a brief conversation on this topic I had with the scientist who pioneered awareness of folic acid’s role in preventing NTDs. (As I recall, it was a Dr. Brady, at Baylor?)

    He expressed concern that we had gone overboard with folate supplementation, that perhaps only a subset of women of childbearing age should be receiving supplementation instead of all people through wholesale fortification of common foodstuffs. And that that other women were perhaps risking increased chance of birth defects via this over supplementation with folate.

  25. GinaPera says:

    P.S. the conversation took place more than 10 years ago; hence my spotty memory. I remember talk of methylation but cannot accurately report the conversation on that score.

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