Is Folate Superior to Folic Acid? A review of the research.
Folate is a hot topic nutrient when talking about preconception and pregnancy due to its role in decreasing neural tube defects (NTD). Early in pregnancy, there is what we know as a neural tube that should close to support appropriate development of the baby's brain and spine.
A few less talked about risk factors of low folate include congenital heart defects, premature birth and low birth weight. I think we can all agree that folate is a very important nutrient!
Like all nutrients, folate works synergistically with other nutrients. Choline, Vitamin B12, Vitamin B6, glycine, riboflavin and magnesium are a few important nutrient-buddies to folate. This blog will focus on folate, just remember that it doesn’t work alone.
The type of folate that is consumed matters. The names folic acid and folate are often used interchangeably, but they are very different!
FOLATE VERSUS FOLIC ACID: WHAT’S THE DIFFERENCE?
Folates are naturally occurring in foods like beans, avocado, brussel sprouts, cabbage and broccoli. There are many types of naturally occurring folates in food, not just one. However, the main folate found in the blood [from food] is 5-methyltetrahydrofolate (5-MTHF). The 5-MTHF form is “active” or ready for the body to use in the many metabolic reactions it is needed for.
Folic acid, on the other hand, is a man-made version of folate that doesn’t have any biological function unless it is reduced to the active form, 5-MTHF. Folic acid is only found in fortified foods, such as fortified grains, and supplements. Folic acid has to be “activated” (aka reduced) in order to be used in the body.
Once the connection was made that adequate folate levels decrease NTD (1965), food fortification of folic acid followed (1996-1998 in USA) along with recommendations for high dose supplementation of folic acid. This public health effort was successful in reducing the cases of NTD by 19-32%.
Remember, folic acid is man made and has to be “activated” (aka reduced) in order to be used in the body. An estimated 40-60% of the population CAN metabolize (“activate”) folic acid for the body to use. This means the other 40-60% CANNOT efficiently metabolize folic acid!
Those that can’t efficiently reduce folic acid into 5-MTHF have genetic variants in the gene that regulate an enzyme called MTHFR. MTHFR stands for
methylenetetrahydrofolate reductase, which is an enzyme that reduces folate into the active form of 5-MTHF. This process is necessary for the body to use folate to prevent NTD.
When folic acid can’t be reduced (“activated”), it hangs out in the body as unmetabolized folic acid (UMFA). Research is showing when consuming folic acid over 200 mcg per day, the body has trouble converting it into the active form 5-MTHF, even if genetic variants aren’t present. UMFA is the reason I use extreme caution with supplementing folic acid. The negative side effects of UMFA are discussed later in this article, but first let’s talk about what we know about “active” folate supplementation.
CAN WE SUPPLEMENT ACTIVE FOLATE INSTEAD OF FOLIC ACID?
There is no specific study looking at 5-MTHF (active folate) supplementation and neural tube defects, but do we need this specific study to know that 5-MTHF can prevent NTD? The major medical organizations might need specific studies to change recommendations that have been in place for decades, but this doesn’t mean we don’t have enough information to know that there is a better option. Especially with the building research on negative side effects from UMFA.
The research shows that 5-MTHF supplementation increases folate levels in the blood as well as and even better than folic acid. Researchers consistently state that, “supplemental 5-MTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs” and 5-MTHF appears to be an efficient and safe alternative to folic acid.
Blood levels have to increase for the nutrient to be able to carry out it’s role in preventing NTDs. So, even though we haven’t seen the funds spent on the research to look at 5-MTHF and NTDs specifically, the biomarker data is very meaningful!
We have observational studies comparing supplementation of folic acid to 5-MTHF during pregnancy. They didn’t look specifically at preventing NTD, but they DID look at blood levels which is how the body uses folate to be able to prevent NTD.
The US FDA approved oral contraceptives to be combined with 5-MTHF in order to reduce the risk of NTDs in women who conceive while taking birth control or soon after. NOT folic acid, but the active 5-MTHF.
It is clear that increased folate in the diet increases folate markers in the blood and we know that folate from food can prevent NTDs. We also know that 5-MTHF supplementation increases folate blood markers, which is the same way folic acid prevents NTDs. There isn’t a reason to believe that a randomized controlled study is necessary to have before recommending 5-MTHF supplementation.
A couple of reasons why the research specifically looking at NTDs and MTHF hasn’t been done:
Money: 5-MTHF is about 260X the cost of folic acid per kilo. Who is going to fund this? Who is benefitting from this research not being done? Remember, folic acid is a man-made, patented substance.
Time: It would take years and thousands of pregnancies to compare folic acid to 5-MTHF supplementation. It is unethical to test 5-MTHF against a placebo.
Those that are saying “I won’t recommend folate until there is a randomized controlled study looking specifically at NTD” simply don’t understand folate metabolism. Based on the building research of UMFA and poor health outcomes, continuing to recommend high doses of folic acid should be strongly cautioned for everyone.
POTENTIAL SIDE EFFECTS OF FOLIC ACID
Research shows that high levels of folic acid can interfere with methylation pathways. Methylation pathways are how nutrients work together to carry out functions like producing energy, supporting detoxification, reducing inflammation, supporting DNA expression and so much more. Methylation is also involved in the prevention of NTD’s during early pregnancy. High levels of folic acid can interfere with methylation pathways both in those that have MTHFR variations and those that don’t.
When our body gets 5-MTHF, it is already available to support the methylation pathways and decrease NTDs or the bazillion other jobs that methylation is necessary for like heart health, neurological function, detox system function, DNA production and more.
Folic acid supplementation and UMFA has been associated with increased risk for allergic diseases, especially respiratory tract allergies among infants and young children. UMFA is found in newborns, we don’t fully understand the effects of UMFA in any human let alone newborns, so supplementation with folic acid during pregnancy should be cautioned.
Circulating UMFA is also associated with a higher risk for neonatal jaundice, infant asthma, developmental delay, and even autism. If we don’t have the ingredients for methylation, like folate, brain development can be impacted.
UMFA is associated with reduced natural killer cell toxicity. Natural killer cells are the first line of defense in the prevention of carcinogenesis and viral infections.
UMFA is associated with elevated homocysteine which is an inflammatory marker. We know that elevated homocysteine levels are a risk factor for miscarriage.
High folic acid supplementation can mask a specific type of anemia called megaloblastic anemia that can occur with low vitamin B12, low folate or both. This is due to how both nutrients are involved in red blood cell production. 5-MTHF or folate from food does not mask megaloblastic anemia.
As stated by folate researcher Obeid:
“The natural form of folate, 5-methylTHF, offers several advantages compared to FA (Table 2): it does not mask B12 deficiency, it is already a biologically active form, it does not cause unmetabolized FA in blood, and it is absorbed and utilized at least as well as FA. Although there are no clinical trials on the effectiveness of 5-methylTHF in preventing NTDs, metabolic studies have shown that 5-methylTHF is a biologically active form of the vitamin and it seems to be at least as effective as FA in improving folate biomarkers. The literature clearly shows that a better food folate intake is associated with better folate markers and that food folate can prevent NTDs (by increasing folate status). FA can prevent NTDs by increasing serum or blood folate level. 5-MethyTHF can effectively increase serum or blood folate markers.”
This table outlines why 5-MTHF is a safer alternative to folic acid. Note that this study was done in 2013.
Obeid, Rima, Holzgreve, Wolfgang and Pietrzik, Klaus. "Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?" Journal of Perinatal Medicine, vol. 41, no. 5, 2013, pp. 469-483. https://doi.org/10.1515/jpm-2012-0256
As you can see, the building research is showing that high doses of folic acid should be cautioned whether there is a MTHFR variation or not. The data we have supports 5-MTHF as a safe supplement for supporting methylation and preventing NTDs.
RECOMMENDATIONS FOR PRECONCEPTION
I know you are probably dying to know “what to do” to support fertility, a healthy pregnancy and healthy baby. Ideally, we want to be supporting our fertility for a minimum of 3-4 months BEFORE trying to conceive for best outcomes with time to conception, healthy pregnancy and healthy baby.
Here are my top tips:
1. Focus on incorporating foods rich in food folate like beans, lentils, avocado, spinach, broccoli, asparagus, beets, whole eggs, liver (duck, beef, chicken & lamb).
2. Limit foods fortified with folic acid like enriched white flour, bread*, pasta, cereals, and other products made with white flour. The goal is to keep intake below 200 mcg of folic acid as this is the amount that starts to interfere with folate metabolism. One slice of bread has about 30 mcg of folic acid while cereals have anywhere from 150 mcg - 400 mcg per cup.
*Whole wheat and whole grains are not typically fortified with folic acid. Opting for bread and grain products with the first ingredient as whole wheat or whole grain can limit folic acid intake.
3. Choose a high quality prenatal vitamin like FullWell (formerly Full Circle Prenatal), Beli, Needed, or Seeking Health Optimal that have 5-MTHF and/or folinic acid as well as the other nutrients supportive of a healthy pregnancy & decreasing NTD risk. Supplement regime should be individualized based on what your body needs, please note that not all of these have iron as this is a very individualized nutrient. Other supplements may be necessary depending on your diet, gut health and fertility history. Work with a fertility dietitian for best outcomes!
It is possible to get enough folate in your diet if you are frequently eating liver and other folate rich foods. The recommendation is at least 600 mcg of food folate a day during pregnancy and minimum of 400 mcg during preconception (although I suggest 600- 800 mcg during the 3-4 months of preconception & when trying to conceive). A supplement is typically a good idea to help fill in the gaps as our diets vary and the quality of food and how well our gut is functioning makes a difference.
TAKEAWAYS:
The majority of the folate in the body is 5-MTHF, which is the most abundant folate in foods.
Folic acid is a man-made version of folate that is found in fortified foods and supplements.
Folic acid has to be converted into 5-MTHF in the body with the help of many other nutrients and an enzyme called MTHFR.
About 40-60% of the population has a MTHFR genetic variation which makes the conversion of folic acid to folate even less efficient.
Side effects of high folic acid intake occur in those with and without MTHFR variations. Side effects seem to be a result of unmetabolized folic acid and include inflammation, poor pregnancy outcomes, altered development of baby and immune system interference.
There are a number of studies showing that 5-MTHF is at least as effective as folic acid in raising folate blood levels. Folate blood levels are necessary to support methylation and therefore decrease NTD risk.
Eating a diet rich in food folate, limiting folic acid fortified foods and including a high quality prenatal with 5-MTHF is recommended.
If you are looking to work with YOUR body to support fertility, please join my waitlist here.
In the meantime, come say hi on IG @the.fertility.dietitian
See you there!
Brooke, MS, RD, LDN
The Fertility Dietitian
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