Should I take Folic Acid or Levomefolic Acid in my prenatal vitamin?

Baby Lying on Back. Photo by Picsea on Unsplash

Bottom Line

Despite all of the research into the benefits of Levomefolic acid, there has never been a single randomized controlled trial looking at its ability to reduce neural tube defects(NTDs)1. Even though it looks like Levomefolic acid works the same as (and sometimes better than) folic acid, prevention of neural tube defects is the #1 reason why you take a prenatal vitamin. It is therefore also the #1 reason why I cannot, as a physician, recommend you take Levomefolic acid instead of folic acid.

Definitions:

  • Synonyms of levomefolic acid: levomefolate L-methylfolate, L-methyltetrahydrofolate, L-MTHF, 5-methyltetrahydrofolate, 5-MTHF, levomefolate, L-5-methyl-THF, (6S)-5-methylTHF
  • NTDs is short for Neural Tube Defects

Folic acid, folate, and levomefolic acid: what’s the difference?

The short answer is that it’s all about chemical structure. Folic acid is a shelf-stable, synthetic version of  the folates found in food. I write “folates” because while the main part of the folate molecule is the same, food contains many different chemical “add ons” to the main part of the folate structure. Levomefolic acid is one of these, but it’s the chemical you get after the body has converted folate (or folic acid) into its usable form2.  

The argument for folic acid:

The main arguments in favor of using folic acid instead of a folate is that it is shelf-stable and has been studied, and proven in many randomized trials, to reduce NTDs. In fact, when the United States started supplementing various foods with folic acid, it saw a 19% reduction in NTDs. The baseline rate of NTDs in the United States is approximately 3 cases per 10,000 live births after the change3, while Canada’s was approximately 6 per 10,0004 in 2002. 

The fact that there are no randomized trials on the effect of supplementing with folate in the prevention of neural tube defects is why the Centers for Disease Control (CDC) says not to use it as a prenatal1. Basically, the only thing that we know for sure prevents NTDs when you put it in a supplement is folic acid.

The argument for levomefolic acid:

There are many reasons to use levomefolic acid instead of folic acid. First of all, folic acid must be turned into levomefolic acid by the body through a series of reactions before it can do its job inside the cell. I will not get into the metabolic pathways but here is a good article that does (Linus Pauling Institute2). 

As you might expect, studies have shown that levomefolic acid increases the amount of folate in the blood similar to that of folic acid5. What’s more, there actually is a relationship between levels of folate in the red blood cells and risk of neural tube defects6,7. So in theory, at least, levomefolic acid should prevent NTDs.

Another reason to favor levomefolic acid might be in people with certain genetic mutations8. One of the most common examples is a mutation in the MTHFR gene which codes for an enzyme in folic acid metabolism. People with this mutation can’t convert folic acid efficiently to levomefolic acid, and they’re stuck with too much homocysteine, a metabolic poison, in the process9.

 Approximately 25% of Hispanics, 10% of Caucasians, 10% of Asians, and 1% of African Americans are born with two copies of this mutation10. Whether or not this is clinically important in NTDs is unclear because the difference between the red blood cell folate concentrations between the normal and mutation groups is fairly small11. Anecdotally, a study was done on 33 couples with this mutation experiencing at least 4 years of infertility. It found that supplementing with levomefolic acid instead of folic acid allowed 13 of the couples to conceive spontaneously9

There are some other possible differences, but those are the biggest and best researched differences without going too far.

Are there any examples of drugs that use Levomefolic acid for prevention of NTDs?

Sort of. The only FDA-approved example I have seen of levomefolic acid being used in this way, aside from in prenatal supplements, is in the oral contraceptive pill Beyaz. This is the pill Yaz with the calcium salt of levomefolic acid added. While I suspect that the marketers would have loved to write “may prevent neural tube defects”, it was only FDA approved to “raise folate levels in women who choose an oral contraceptive for contraception”12. That was in 2010 and, amazingly, still no new studies have been published.

Conclusion

On the surface, I’ll admit that levomefolic acid seems like the better choice. In fact, it seems better in almost every way, except the one that counts the most: preventing neural tube defects. If you want an actual answer to this question, we need to do the research. If you can’t sleep at night because you just need to know, I suggest you contact the National Institutes of Health (USA) or Health Canada. If you could get them to fund a randomized controlled trial of levomefolic acid versus folic acid in preventing neural tube defects, I’ll bet it would change folic acid supplementation around the world.

You might also like to read this blog post by Chris Kesser, who uses similar science to come to a different conclusion. The good news is that supplements do exist with both forms of folate so ultimately, the choice is yours. Please leave a comment below!

References

 

Photo credit: Picsea on Unsplash

  1. CDC. General Information About NTDs, Folic Acid, and Folate. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/folicacid/faqs/faqs-general-info.html. Published October 22, 2018. Accessed September 16, 2019.
  2. Folate. Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/folate. Published April 22, 2014. Accessed September 17, 2019.
  3. Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA. 2001;285(23):2981-2986. doi:10.1001/jama.285.23.2981
  4. Ray JG, Meier C, Vermeulen MJ, Boss S, Wyatt PR, Cole DEC. Association of neural tube defects and folic acid food fortification in Canada. Lancet Lond Engl. 2002;360(9350):2047-2048. doi:10.1016/S0140-6736(02)11994-5
  5. Venn BJ, Green TJ, Moser R, McKenzie JE, Skeaff CM, Mann J. Increases in blood folate indices are similar in women of childbearing age supplemented with [6S]-5-methyltetrahydrofolate and folic acid. J Nutr. 2002;132(11):3353-3355. doi:10.1093/jn/132.11.3353
  6. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA. 1995;274(21):1698-1702. doi:10.1001/jama.1995.03530210052030
  7. Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, Scott JM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med. 1993;86(11):703-708.
  8. Obeid R, Holzgreve W, Pietrzik K. Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? J Perinat Med. 2013;41(5):469-483. doi:10.1515/jpm-2012-0256
  9. Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series. J Assist Reprod Genet. 2018;35(8):1431-1435. doi:10.1007/s10815-018-1225-2
  10. Office of Dietary Supplements - Folate. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/. Accessed September 14, 2019.
  11. 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. Am J Clin Nutr. 2015;101(6):1286-1294. doi:10.3945/ajcn.114.099994
  12. Fruzzetti F. Beyaz®: An Oral Contraceptive Fortified with Folate. Womens Health. 2012;8(1):13-19. doi:10.2217/WHE.11.68

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