Article at a Glance
- Folate (vitamin B9) is an essential nutrient, and studies show it is especially important during pregnancy where supplementation, traditionally with folic acid, decreases the risk for many birth defects.
- Folic acid is a synthetic form of folate.
- The body converts folate and folic acid into methylfolate, which is the bioavailable form of folate the body can use.
- Those with certain variants in the MTHFR genes cannot convert folic acid into methylfolate, which can cause folic acid to reach toxic levels.
- In these cases, it is better to supplement with methylfolate rather than folic acid.
Folate (vitamin B9) is an essential nutrient required for DNA replication, amino acid synthesis, and a range of enzymatic processes in the body. As such, it’s no surprise that we need more folate during times of rapid growth and development, such as in pregnancy. For most individuals, that means reaching for folic acid pills.
In this post, I examine whether it’s OK to take this synthetic version of folate – folic acid – during pregnancy, especially if you have a common variant in the MTHFR gene.
If you don’t know whether you have an MTHFR “mutation” see our post on how to find out.
For more on the science of MTHFR, see this post.
- What is folate and why do we need it?
- Folate vs. Folic Acid – what’s the difference?
- Genetic variants and pregnancy
- What does it all mean for folate and pregnancy?
- When to start taking folate
- Benefits of L-methylfolate
- Are there any risk in taking too much folic acid?
- The takeaway
What is folate and why do we need it?
There’s no doubt that folate is an important vitamin, especially in pregnancy. Birth abnormalities have been dramatically reduced in countries such as Canada and the US where folic acid fortification of staple foods was made mandatory in 1998 (R).
Many other countries, some 53 in total, now have laws mandating folic acid fortification, but the implementation of fortification is somewhat haphazard. Indeed, research suggests that even in countries that fortify foods, many people capable of becoming pregnant are still not getting enough folate to meet their needs (R). If you don’t eat a lot of processed foods, and tend to skimp on your leafy greens, there’s an even greater chance you’re missing out on folate.
Folate deficiency during pregnancy not only affects the health of the birth parent (causing anemia and peripheral neuropathy), it can also cause spina bifida and other congenital abnormalities in the fetus. A lack of folate in pregnancy can even increase the risk of spontaneous abortion or miscarriage (which is often the body’s way of terminating a pregnancy where the fetus has significant abnormalities).
So, how much folate do we actually need for a healthy pregnancy? The US National Institutes of Health (NIH) and Institute of Medicine (IOM) recommend a daily intake of:
- 400 µg to 1000 µg folic acid daily prior to conception
- 600 µg of folic acid daily during pregnancy
- 500 µg of folic acid daily during lactation.
If you’re at high risk of having a child with a neural tube defect (NTD), the NIH/IOM recommend you take 5 mg of folic acid, commencing prior to conception and continuing throughout pregnancy and postpartum (note that you should not carry on with this high of a dose after pregnancy).
People at high risk of an NTD include those with a personal or family history of NTDs and/or anyone taking medications that deplete folate, such as anticonvulsant drugs. In general, however, it is now widely acknowledged that most people struggle to get enough folate from diet alone to meet the increased needs of pregnancy. As such, folate supplementation is necessary to support a healthy pregnancy.
The next question, then, is what kind of folate supplementation is best?
Folate vs. Folic Acid – what’s the difference?
Folic acid and folate are often thrown around as if they are interchangeable terms, but they’re not. Folate is an umbrella term that encompasses several related compounds in the vitamin B group that share a similar structure.
Folic acid is a synthetic form of folate that became popular because it is stable in supplement form and can be used to fortify foods. The folate found naturally in food is not stable enough to be used in supplements (without modification) or for fortification. And, the amount of folate can vary considerably in the diet, making supplements a convenient way to ingest a minimum amount of folate each day.
The body converts folate to usable form 5-MTHF
Food folate is found in leafy green vegetables, legumes, citrus fruit, and in egg yolks and liver. After ingestion, both food folate and folic acid must be converted into metabolically active forms of folate before your body can do anything useful with them. L-5-Methyltetrahydrofolate (L-methylfolate, or 5-MTHF) is the predominant active form of the nutrient in humans and is created through the activity of several enzymes. L-methylfolate acts as a methyl donor in one-carbon transfer reactions, including those involved in DNA methylation, purine/pyrimidine synthesis during DNA and RNA assembly, and in homocysteine metabolism.
The conversion of food folate and folic acid to L-methylfolate is a little convoluted. First, these compounds are converted into dihydrofolate (DHF) through enzymatic reduction. Then, the enzyme dihydrofolate reductase (DHFR) converts DHF into tetrahydrofolate (THF). THF is then converted into the biologically active L-methylfolate by the enzyme methylenetetrahydrofolate reductase (MTHFR).
So, if both food folate and folic acid have to undergo this conversion process, does it really matter where you get your folate from? In short, yes, it does.
Study: methylfolate more effective than folic acid
In one recent double-blind, randomized, placebo-controlled trial involving 144 women, a readymade L-methylfolate supplement was deemed more effective than folic acid at increasing red blood cell folate concentrations (R). Why might this be? Well, for one thing, a small majority of us appear to have a single nucleotide polymorphism affecting the metabolism of folate and folic acid to active L-methylfolate. This is the famous “MTHFR mutation” you’ve heard so much about.
Genetic variants and pregnancy
The most common MTHFR mutation is a nucleotide exchange in position 677 of the MTHFR gene, (C<T). This involves amino acid substitution from alanine to valine in position 222. People with the wild-type mutation (677CC) have uninhibited MTHFR enzyme activity. 6, 7, 8. People who carry two abnormal copies of this gene (homozygous 677TT) have around a 65% decrease in normal MTHFR enzyme activity. Heterozygous 677CT people have a loss of activity of around 30% (R). In homozygous carriers of another variant (MTHFR 1298A->C), activity of the enzyme may be reduced to 68% of the wild-type activity (R).
Amongst white people, around 1 in 10 are homozygous (677TT) and 40 % heterozygous (677CT), with the other half enjoying uninhibited MTHFR activity thangs to their wild-type (677CC) variant (R). Even if you’re not planning on becoming or are already pregnant, decreased MTHFR activity can be harmful to health. That’s because decreased MTHFR activity increases the risk of elevated homocysteine concentrations and reduces the availability of S-adenosyl methionine as a methyl group donor.
Fortunately, even for those of us with diminished MTHFR activity, increasing our intake of folate-rich foods, or straight-up supplementing with coenzymated L-methylfolate can help us keep our active folate levels up and our homocysteine levels in check.
Other troublemakers to watch out for
Taking folate in the form of L-methylfolate also overcomes another potential issue with folate metabolism, namely a lack of DHFR activity. As noted above, DHFR is an intermediary step in the folate metabolic cascade, and some people have a variant in the DHFR gene (a 19-base pair deletion) that interferes with folate metabolism. This gene variant also affects the transport of reduced folate across the placenta (R).
More recently, researchers have also identified another genetic variation that appears to link folate and problems in pregnancy. The SHMT1(1420)T variant reduces the transcriptional activity of serine hydroxymethyltransferase 1 and is associated with an increased risk of spontaneous pre-term birth. What’s more, the likelihood of spontaneous pre-term birth is significantly higher in people with this genetic variant if they also have low folic acid intake.
Specifically, white carriers of SHMT1(1420)T had a 90% increased likelihood of spontaneous pre-term birth, while carriers of another genetic variant (MTRR(66)A) had double the risk of early birth. In black women with the SHMT1(1420)T variant, only those with the lowest intake of dietary folate had an increased risk of spontaneous pre-term birth (the risk more than doubled, with an odds ratio of 2.6) (R)
What does it all mean for folate and pregnancy?
Given what we now know about a handful of genes involved in folate metabolism, is it better to supplement with coenzymated folate instead of folic acid prior to and during pregnancy?
If you have a confirmed MTHFR “mutation,” the answer is yes. In these cases, methylfolate is the clear winner as those who carry MTHFR genes cannot properly metabolize folic acid. For these people, folic acid can be toxic.
As part of your pre-conception plan, you may well want to undergo genetic testing to see which copies of the MTHFR, DHFR, and SHMT genes you carry. This could help you determine if folic acid supplements are likely to work for you, or if a coenzyme L-methylfolate supplement is necessary instead.
That said, if your only option is to increase dietary folate or take folic acid supplements, definitely do so if you’re trying to conceive or are already pregnant. And, ideally, try to supplement with folic acid for at least a year prior to conception. Research shows that doing so could reduce your risk of spontaneous pre-term birth by up to 78% (R).
For many people, food fortification and folic acid supplements at a level of 800 mcg per day are likely to be sufficient to maintain a good level of active folate. Indeed, shortly after folic acid fortification came into effect in Canada and the US, researchers observed a significant increase in the concentrations of erythrocyte (blood cell) folate among women of childbearing age, as well as a decrease in neural tube defects in newborns (R, R).
When to start taking folate
Recommendations differ for folate in pregnancy, and it’s good to start taking folate supplements well before you become pregnant:
- If you’re planning to conceive and have no known health risks – eat a diet rich in folate and take a folic acid or, ideally, an L-methylfolate supplement providing 400-1000 mcg per day for at least 2-3 months prior to becoming pregnant and through pregnancy and while nursing your infant.
- If you have a family or personal history of neural tube defects or other high-risk factors – eat folate-rich foods and supplement with 5 mg (5000 mcg) of folic acid or, ideally, L-methylfolate daily beginning at least 3 months prior to conception until 10-12 weeks post-conception. After that, take 400 mcg to 1000 mcg daily through to nursing.
Because increased folate intake can mask symptoms of vitamin B12 deficiency, it’s a good idea to also supplement with vitamin B12, as methylcobalamin, in pregnancy (especially if you don’t eat animal-derived foods very often or at all). Vitamin B12, iron, and folate demands all increase in pregnancy, in part because the body has to dramatically increase its production of red blood cells and hemoglobin in a process called erythropoiesis.
Benefits of L-methylfolate
Although studies are still in their infancy regarding the potential advantages of L-methylfolate over folic acid supplements, the evidence does point to benefits from taking the ready-made coenzyme form of folate.
One study found that hemoglobin levels were higher at the time of delivery in women who received prenatal medical food providing 1.13 mg of L-methylfolate in addition to 0.4 mg of folic acid and 500-1000 mcg of vitamin B12, compared to women who only received standard prenatal vitamins providing 0.8-1 mg of folic acid and 0-12 mcg of vitamin B12. The women receiving L-methylfolate also had a much lower incidence of anemia at the end of the second trimester compared to those taking standard prenatal vitamins (39.7% vs. 74.1%) (R).
Coenzyme L-methylfolate may also be the better option for anyone taking folic acid antagonists, which are associated with a significantly higher rate of complications in pregnancy, including pre-eclampsia, placental abruption, fetal growth restriction, and fetal death (R). All of these complications have their root in the early days of pregnancy, strongly implicating low levels of active folate at this time.
Drugs to watch out for include DHFR inhibitors such as sulfamethoxazole-trimethoprim, as well as other folic acid antagonists including:
- Anticonvulsant medications (phenobarbital, phenytoin, primidone, and carbamazepine)
- Spasmophen (an antispasmodic drug that contains low doses of phenobarbital)
Are there any risk in taking too much folic acid?
Prior to conception, a well-meaning health care practitioner may tell you to supplement with high levels of folic acid just in case you have a genetic variant that inhibits folate metabolism. Is it dangerous, though, to take folic acid at levels above the normal 400-800 mcg recommendation?
Yes. As John and Aaron have written about previous on this blog, long term use of high dose folic acid supplements has been linked to an increased risk of cancer. The threshold dose in most of the studies is 0.8mg per day, but there was no increased risk when the folate was combined with a multivitamin, and Aaron has theorized that this is because B2 is protective. The bottom line here is that folate supplementation is generally regarded as a good idea during pregnancy, however, think twice before supplementing at high doses for a period of years.
Another area of concern when it comes to supplementing with high levels of folic acid is that this can mask symptoms of vitamin B12 deficiency which can leave you vulnerable to irreversible nerve damage. If you also supplement with vitamin B12, chances are that this will not be an issue even if folic acid intake is high.
The next area of concern over high folic acid intake is a bit more complicated. Some researchers worry about the possible dangers of unmetabolized synthetic folic acid in people with poor folate conversion capacity.
Unmetabolized folic acid and pregnancy
In one study, 1 in 3 adults were found to have unmetabolized folic acid circulating in their blood, and this was associated with an increased risk of anemia in those adults who consumed alcohol (R). Those who had detectable levels of circulating unmetabolized folic acid also had lower scores on cognitive testing compared to those without detectable levels of circulating unmetabolized folic acid.
In another study, this time involving 30 healthy Brazilian women, those who received 5 mg of folic acid daily for 90 days had a 5-fold increase in serum folate concentrations, as well as an 11.9-fold and 5.9-fold increase in unmetabolized folic acid levels after 45 and 90 days respectively (R).
The researchers in the Brazilian study also observed significant reductions in the number and activity of Natural Killer cells (part of the immune system) after 45 and 90 days of folic acid supplementation. This suggests that folic acid supplementation may adversely affect immune system function in some people (R), which would leave them vulnerable to infection during pregnancy. Although this possible link between excess unmetabolized folic acid and poor pregnancy outcomes is largely theoretical at this point, other research has found that decreased levels of NK cells in pregnancy are associated with an increased risk of pregnancy loss (R).
Interestingly, results from longer studies show that levels of unmetabolized folic acid start to drop after a while. This suggests that, if given enough time, the body can increase folic acid metabolism and decrease levels of circulating unmetabolized folic acid. If this is, indeed, the case, it would have ramifications for anyone starting to take high dose folic acid just prior to conception.
In conclusion, then, in the absence of thorough genetic testing showing that you can efficiently convert folic acid to L-methylfolate, it seems smart to take an L-methylfolate supplement daily starting 2-3 months prior to conception and continuing through pregnancy and while nursing. Even better, opt for a comprehensive prenatal formula that provides active coenzyme L-methylfolate. If you don’t have access to such supplements, your next best option may well be to take 5 mg of folic acid daily for a year prior to conception and for the first 10-12 weeks of pregnancy, and then to decrease this to 0.4-1 mg of folic acid daily throughout the rest of your pregnancy.
As always, before you take any supplements, be sure to talk to your health care practitioner, especially if you have existing medical conditions or are already pregnant.