Folate vs. Folic Acid In Pregnancy – Why The Difference Matters!

folate-vs-folic-acid-pregnancy

If you’re pregnant or trying to conceive, your doctor has most likely advised you to start taking folic acid ASAP, either as part of a prenatal multivitamin or as a separate supplement.

Why?

Evidence shows that inadequate folate status during pregnancy is associated with an increased risk of fetal neural tube defects (NTDs) that affect the baby’s brain, spine, and spinal cord (like spina bifida, or anencephaly). New research suggests that folate may also play a role in preventing facial clefts, certain heart defects, and possibly preterm birth.

According to the ACOG (the American Congress of Obstetricians and Gynecologists):

Folic acid, also known as folate, is a B vitamin that is important for pregnant women. Before pregnancy and during pregnancy, you need 400 micrograms of folic acid daily to help prevent major birth defects of the fetal brain and spine called neural tube defects.”

The WebMD states:

Folic acid is a pregnancy superhero! Taking a prenatal vitamin with the recommended 400 micrograms (mcg) of folic acid before and during pregnancy can help prevent birth defects of your baby’s brain and spinal cord. Take it every day and go ahead and have a bowl of fortified cereal, too.”

I’m not going to argue the importance of folate here. 

Folate plays a crucial role in virtually everything your body does and is especially important in pregnancy. But before you down that bowl of fortified cereal and chase it with a prenatal vitamin containing folic acid, hold it for just a second…

FACT: Folic acid can help reduce the risk of neural tube defects.

FACT: Folic acid can help reduce the risk of neural tube defects, but this finding comes with a few IMPORTANT caveats.

And that’s what I want to talk about.



But first, let’s get something straight.

The terms FOLIC ACID and FOLATE are often used interchangeably as if they were the same thing, even among healthcare professionals.

IS FOLATE AND FOLIC ACID THE SAME THING? 

Short answer: NO.

What is FOLATE?

Folate is the natural form of an essential nutrient otherwise known as vitamin B9 that plays a key role in many metabolic pathways in the body.

Even though folate is usually referred to in a singular form, it comprises of a large group of similar compounds.

Natural folate can be found in some foods or in food supplements containing folate.

What is FOLIC ACID?

Folic acid is a synthetic form of vitamin B9 that’s virtually nonexistent in nature.

Folic acid can be found in food supplements (including prenatal vitamins) and processed fortified foods.*

*Following a mandate from 1996 (fully implemented in 1998), folic acid is added to conventional (and some organic) enriched grain products in the U.S. (bread, rolls, pastries, pasta, breakfast cereal, etc.) and in some other countries worldwide with the intention to increase folate levels not so much in the general population but mainly in the females of childbearing age.

WHY WAS/IS THE POPULATION DEFICIENT IN FOLATE?

In order to answer this question, we’ll have to go back in time. (That’s almost always fun, isn’t it?)




The wheat flour has changed.

The way grain is milled commercially has changed dramatically from the old days and so has the flour we use.

The wheat kernel is made up of 3 components:

  1. The BRAN is the outer part of the kernel and contains large amounts of B vitamins, some protein, phytonutrients, trace minerals and dietary fiber.
  2. The GERM is the sprouting and central part of the kernel. It’s packed with healthy fats, fiber, folate and many other B vitamins, protein, and minerals.
  3. Then there is the ENDOSPERM, the largest portion of the kernel, which contains high amounts of carbohydrates and small amounts of vitamins and minerals.

Originally, small-operation stone milling typically powered by wind or water was the only way to turn grain into flour. The flour milled in this way used all three vital parts of the kernel and retained much of its nutritional value.

The problem was that it had a relatively short shelf life for which the GERM was responsible, given it contains oil. (Oils speed up oxidation which results in rancidity.)

Looking for means to mass produce, automated flour mills were gradually introduced, with the steam roller mill invented in 1865 changing the flour forever – for better and for worse.

folate-vs-folic-acid-pregnancy

During processing, all three parts of the wheat berry were separated in roller milling. With much of the BRAN and the GERM removed, only the starchy part – the ENDOSPERM – was used to make commercial flour.

PRO: This resulted in a dramatically extended shelf life.

CON: The flour was stripped of much of its nutrients.

The results of modern industrial milling led to higher profits and increase in production but also to a surge in health issues including miscarriages and birth defects.

The government knew and had to do something.

In 1941, the U.S. federal government launched a flour enrichment program, calling for a flour fortification with iron and some B vitamins (thiamin, riboflavin, and niacin) which were some of the nutrients lost in the milling process. 

In 1998, folic acid became the most recent addition to the mandate due to evidence showing that the risk of neural tube defects in infants dropped when mothers took more folic acid before getting pregnant.

In case you wonder why synthetic folic acid is used in food fortification rather than actual folate, it’s because folic acid is (1) more stable; (2) much cheaper to produce than folate.

And, here we are….

So, what exactly is the problem with folic acid???




FOLATE VS. FOLIC ACID – BIOAVAILABILITY

If you research folic acid, you’re bound to find this: “Folic acid is more bioavailable than natural folate.” 

There are two reasons folic acid is considered to be more bioavailable than folate:

  1. Folic acid is more stable. It doesn’t degrade as quickly as natural folates do after harvest (during food storage and preparation).
  2. While folic acid only exists in a monoglutamate form (containing only 1 glutamate), the majority of natural folates are polyglutamate chains (meaning they contain more than 1 glutamate) which is believed to hamper natural folate bioavailability. (This, however, doesn’t appear to be the case, according to science.1, 2)

Until fairly recently, studies were indicating that synthetic folic acid is much more bioavailable thus more efficient than naturally occurring dietary folate. (If this sentence makes no sense to you, you’re not alone.)

Not surprisingly, new research shows that the bioavailability of natural folates is up to 98% (WAY higher than previously assumed), and that consuming a diet rich in naturally occurring folates is actually much more effective than once believed.3, 4, 5 (Who woulda thunk?)

This doesn’t negate any previous findings but shows that several pre- and post-absorptive factors play a significant role in folate bioavailability. These can include specific forms of folate, the cellular matrix of the food consumed, as well as genetic polymorphism (more on that in a bit).

FOLATE VS. FOLIC ACID – ABSORPTION

FOLIC ACID is not readily usable – but some natural FOLATE is. Why is this important? 

Folic acid may be considered more bioavailable for the reasons mentioned above, but that doesn’t mean it can be used by the body right away.



Instead, folic acid needs to be converted into a biologically active form that the body CAN use which is methylated folate = L-Methylfolate in a process called methylation.

L-Methylfolate is also known as:

  • Methylfolate
  • 5-Methylfolate
  • 5-Methyltetrahydrofolate
  • L-5-Methyltetrahydrofolate
  • 6(S)-5-Methyltetrahydrofolate
  • L-MTHF
  • 5-MTHF
  • L-5-MTHF
  • 6(S)-5-MTHF
  • 5-CH3-H4folate
  • 5-Methyl THF (as shown below)

Basically, L-Methylfolate is the final cycle of the methylation pathway. It’s the end result of the folate conversion and the functional form of folate that the body can use to reap the benefits.

Folic acid metabolism (some interactions not shown).

Folic acid metabolism (some interactions not shown).

When consumed, folic acid must be reduced – first to dihydrofolate (DHF), then to tetrahydrofolate (THF), before being methylated. Each step of the conversion is dependent on specific enzymes, with the last step of the conversion relying on the MTHFR enzyme (MTHFR being the acronym for methylenetetrahydrofolate reductase).

TECHNICALLY… Both natural folate and synthetic folic acid fall into the same loop of methylation cycle.

The difference here is that folate occurs in nature in a wide range of reduced forms (unlike unreduced folic acid), with many foods naturally containing high levels of L-Methylfolate (methylated, usable form of folate). Another minor difference is that while folate is absorbed in the small intestine, folic acid is converted into L-Methylfolate in the liver instead.6,

Overall, the most abundant natural folate classes are [reduced and methylated] 5-Methyltetrahydrofolate (5-Methyl THF; 5-CH3-H4folate), [reduced] 5- and 10-Formyltetrahydrofolate (5,10-Formyl THF), and [reduced] tetrahydrofolate (THF).8, 9

You cay say that there is folic acid that needs to be reduced before being methylated, and various forms of natural folate that differ in the reduction extent from which some is already methylated (readily usable) and some unmethylated (reduced but still needing to go through the last and final MTHFR pathway).

Virtually none of the folate in food is present in the form of unreduced folic acid.

Without exception, several processes and cofactors must play out in order to convert folic acid into L-Methylfolate.

For some of us, the conversion may not happen so easily.

In a significant portion of the population, the MTHFR enzyme – a key player in methylation – may not be very efficient due to specific deficiencies.

It turns out that an estimated 30-50% of the population (if not more) carries a mutation in the MTHFR gene. 

folate-vs-folic-acid-pregnancy

What’s the relationship between the MTHFR gene / MTHFR enzyme?

In short, we’re all born with the MTHFR gene. It’s passed down to us from our parents.

The MTHFR gene is responsible for producing the MTHFR enzyme that helps convert folic acid and some folate into L-Methylfolate, a biologically active form of folic acid/folate.

Some of us carry a mutation in the MTHFR gene which can interfere with methylation. There are several common mutations that can happen with this gene and quite possibly many more to be discovered.

On its own, having an MTHFR mutation isn’t concerning because the gene isn’t always triggered. It’s entirely possible to have the gene mutation without any related health issues. Genetics certainly play a part, but the environment we live in and our lifestyle choices and diet are just as important, if not more!

However, those that ARE affected by imbalanced methylation may have a much harder time converting synthetic folic acid and some natural folate into methylfolate. Which is a BIG problem especially in pregnancy when sufficient folate intake is crucial.



It’s possible to have more than one mutation, with some mutations being more problematic than others. In general, the more variations of MTHFR mutations you have, the more difficult the process of methylation might be for you.

Depending on specific MTHFR mutations, your body may be up to about 70% less efficient in converting folic acid and some folate into methylfolate. (Some sources state even lower efficiency rates, but the numbers aren’t consistent across the board.)

But that’s not all to worry about.

If methylation is impaired, unmetabolized folic acid can be found circulating in the blood (in potentially very high levels). In reality, even small amounts of folic acid can cause a build-up of unmetabolized folic acid in the bloodstream.

There are theoretical health risks associated with unmetabolized folic acid but this topic needs to be explored more before conclusions can be drawn.

HOW SAFE IS FOLIC ACID SUPPLEMENTATION + FOOD FORTIFICATION?

Realistically, we are yet to find out.

Scientists are increasingly wondering if the scale of folic acid fortification and supplementation we see today is necessary, and whether it could cause more harm than good. There is growing concern that folic acid intake could result in detrimental effects, particularly in susceptible individuals.

Although it’s a controversial subject, folic acid supplementation/food fortification has been identified as a potential risk factor for some types of cancers.10, 11, 12, 13, 14, 15

While the tolerable upper limit for folic acid intake is set at 1,000 mcg/day for all adults (pregnant or not), many adults regularly exceed this upper limit just from consuming fortified foods alone. If they take a multivitamin that contains folic acid, that can definitely put them over the top. Many OTC and prescription prenatal vitamins contain upwards of 800 mcg of folic acid per dose. That’s a lot of folic acid for someone also consuming fortified foods.

The health implications of high folic acid intake aren’t fully known yet, but ongoing research is indicating there might be some cause for concern.16, 17, 18, 19




FOLATE VS. FOLIC ACID IN PREGNANCY – WHAT’S THE SOLUTION?

To optimize your folate levels in pregnancy (and beyond!) without knowing your MTHFR status:

(1) Consume plenty of foods rich in folate.

Natural folate from folate-rich foods has significant advantages over synthetic folic acid. It comes bundled with other micronutrients for better absorption, and much of it is supplied in a methylated, bioavailable form.

(2) Take prenatal vitamins / supplements containing folate rather than folic acid.

Read labels carefully. Many labels show folate but contain folic acid, including some of the more expensive prenatal vitamins.

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(3) Talk to your doctor about having the levels of homocysteine tested in a simple blood test.

If they seem fine, nothing needs to be done (even if you have a variation in the MTHFR gene).

If the levels are elevated, you may need to take supplements that will address your needs. (Many doctors like to prescribe high doses of folic acid to remedy this problem (while it was folic acid that wasn’t working in the first place). If that’s your case, I suggest you take the time to research MTHFR in depth and seek the help of a professional that understands methylation deficiency including upstream and downstream folate metabolism.)

SHOULD YOU GET TESTED FOR MTHFR MUTATIONS?

This genetic test can be done either through your healthcare provider (your insurance may cover the cost) or independently through a private lab using saliva or a blood sample.

23andMe is probably the most popular company for private genetic testing, but you’d need to run your raw data file through a genetic reporting service like Genetic Genie, NutraHacker, or something similar to access your methylation profile.

If you’re interested in getting tested, keep in mind that just having an MTHFR mutation alone won’t necessarily mean that your MTHFR enzyme isn’t functioning well.

Also, you should think ahead of time about how having your DNA stored in a centralized genetic database makes you feel, and what the future implications of sharing your DNA may be. Once it’s out there, it’s out there. Even if you didn’t give consent to share.

Disclosure: This article is not intended for the treatment or prevention of any disease or as a substitute for a medical treatment. Always consult your medical provider.

 


Source:

  1. Alida Melse-Boonstra, Angelika de Bree, Petra Verhoef, Anne L. Bjørke-Monsen, W.M. Monique Verschuren; Dietary Monoglutamate and Polyglutamate Folate Are Associated with Plasma Folate Concentrations in Dutch Men and Women Aged 20–65 Years. The Journal of Nutrition, Volume 132, Issue 6, 1 June 2002, Pages 1307–1312; https://doi.org/10.1093/jn/132.6.1307.
  2. Folate & Folic Acid; https://courses.lumenlearning.com/suny-nutrition/chapter/11-1-folate-folic-acid/.
  3. Winkels RM, Brouwer IA, Siebelink E, Katan MB, Verhoef P; Bioavailability of food folates is 80% of that of folic acid. Am J Clin Nutr. 2007 Feb;85(2):465-73.
  4. Brouwer IA, van Dusseldorp M, West CE, Meyboom S, Thomas CM, Duran M, van het Hof KH, Eskes TK, Hautvast JG, Steegers-Theunissen RP; Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. J Nutr. 1999 Jun;129(6):1135-9.
  5. Folate & Folic Acid; https://courses.lumenlearning.com/suny-nutrition/chapter/11-1-folate-folic-acid/.
  6. Patanwala I, King MJ, Barrett DA, Rose J, Jackson R, Hudson M, Philo M, Dainty JR, Wright AJ, Finglas PM, Jones DE; Folic acid handling by the human gut: implications for food fortification and supplementation. Am J Clin Nutr. 2014 Aug;100(2):593-9. doi: 10.3945/ajcn.113.080507. Epub 2014 Jun 18.
  7. Wright AJ, Dainty JR, Finglas PM; Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr. 2007 Oct;98(4):667-75. Epub 2007 Jul 9.
  8. Paul Finglas, Anthony J.A. Wright; Folate bioavailability and health. Article in Phytochemistry Reviews 1(2):189-198, May 2002; DOI: 10.1023/A: 1022559417212.
  9. Nicolas Delchier, Anna‐Lena Herbig, Michael Rychlik, Catherine M.G.C. Renard; Folates in Fruits and Vegetables: Contents, Processing, and Stability. First published: 17 February 2016 https://doi.org/10.1111/1541-4337.12193.
  10. Shaidah Deghan Manshadi, Lisa Ishiguro, Kyoung-Jin Sohn, Alan Medline, Richard Renlund, Ruth Croxford, Young-In Kim; Folic Acid Supplementation Promotes Mammary Tumor Progression in a Rat Model. Published: January 21, 2014; https://doi.org/10.1371/journal.pone.0084635.
  11. Baggott JE, Oster RA, Tamura T; Meta-analysis of cancer risk in folic acid supplementation trials. Cancer Epidemiol. 2012 Feb;36(1):78-81. doi: 10.1016/j.canep.2011.05.003. Epub 2011 Oct 21.
  12. Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH; A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1325-9.
  13. Kim YI; Does a high folate intake increase the risk of breast cancer? Nutr Rev. 2006 Oct;64(10 Pt 1):468-75.
  14. Anna Ly, Hanna Lee, Jianmin Chen, Karen K. Y. Sie, Richard Renlund, Alan Medline, Kyoung-Jin Sohn, Ruth Croxford, Lilian U. Thompson and Young-In Kim; Effect of Maternal and Postweaning Folic Acid Supplementation on Mammary Tumor Risk in the Offspring. DOI: 10.1158/0008-5472.CAN-10-2379 Published February 2011.
  15. Curtis J. Henry, Travis Nemkov, Matias Casás-Selves, Ganna Bilousova, Vadym Zaberezhnyy, Kelly C. Higa, Natalie J. Serkova, Kirk C. Hansen, Angelo D’Alessandro, and James DeGregori; Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis. Haematologica. 2017 Dec; 102(12): 1985–1994; Prepublished online 2017 Sep 7. doi: 10.3324/haematol.2017.171074.
  16. Karen E Christensen, Leonie G Mikael, Kit-Yi Leung, Nancy Lévesque, Liyuan Deng, Qing Wu, Olga V Malysheva, Ana Best, Marie A Caudill, Nicholas DE Greene, and Rima Rozen; High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015 Mar; 101(3): 646–658. Published online 2015 Jan 7. doi: 10.3945/ajcn.114.086603.
  17. Selhub J, Rosenberg IH; Excessive folic acid intake and relation to adverse health outcome. Biochimie. 2016 Jul;126:71-8. doi: 10.1016/j.biochi.2016.04.010. Epub 2016 Apr 27.
  18. Darrell Wiens, Catherine DeSoto; Is High Folic Acid Intake a Risk Factor for Autism? – A Review. Brain Sci. 2017 Nov; 7(11): 149. Published online 2017 Nov 10. doi: 10.3390/brainsci7110149.
  19. Patel KR, Sobczyńska-Malefora A; The adverse effects of an excessive folic acid intake. Eur J Clin Nutr. 2017 Feb;71(2):159-163. doi: 10.1038/ejcn.2016.194. Epub 2016 Oct 12.

 

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