Doubts over the safety of folic acid have been mounting for a few years; indeed, we at Igennus removed folic acid from a formulation last year. New research linking high folic acid intake during pregnancy to greater risk of Autism Spectrum Disorder (ASD) makes even more compelling the need for companies to transition to using the more bioavailable, safer form that we consume in foods – folate.
What did the study actually find?
Of 1,391 mothers recruited between 1998 and 2013, a total of 107 children were diagnosed with ASD. Although maternal multivitamin supplementation (3–5 times/wk) was associated with significantly lower risk of a diagnosis of ASD overall, 10% of mothers were found to have folate levels in excess of 59nmol/L, which was associated with double the risk of ASD in their children (HR: 2.27; p=0.007). 6% of mothers also had vitamin B12 levels in excess of 600 pmol/L, which tripled ASD risk (HR: 3.01; p=0.001). Alarmingly, having excessive levels of both nutrients increased the risk of ASD by 17.6 times (HR: 17.56; p<0.001). The authors attribute higher levels of these vitamins to folic acid-fortified food and supplements.
Folate in food vs folic acid in most supplements
Folic acid supplementation before and during pregnancy has long been considered to be a requirement to reduce the risk of neural tube defects that can lead to conditions such as spina bifida. Folic acid is the synthetic form of the nutrient folate, which is the form used in the body and found in foods. Most pregnancy care supplements and fortified foods on offer contain folic acid, but rather than give up on important prenatal care supplements, more recent formulations that contain the bioavailable and safe form, folate, are becoming more easily available. Crucially, pregnant women, and many others who would benefit from folate’s numerous benefits, should not give up on this vital nutrient!
Why bioavailability is so important
Unlike natural folates, which are metabolised in the small intestine before being used by the cells, folic acid is processed in the liver and requires a biological catalyst or enzyme called dihydrofolate reductase. The activity of this enzyme in the liver is actually very low and if intake of folic acid is too high, this can result in the accumulation of large amounts of inactive folic acid. It does not require high doses of folic acid (only 200ug) daily for the enzyme dihydrofolate reductase to become overwhelmed, meaning that any unprocessed folic acid could pass directly into the blood. Having this unrecognisable, inactive form of folic acid in the blood can alert the immune system, which then tries to destroy and eliminate this unwanted ‘invader’. This becomes a problem if the immune system is activated for too long or too often (as is the case with long-term folic acid supplementation), as the body can start to attack and damage the very cellular mechanisms that absorb folate and prevent its transport to the brain (in a bid to protect it from said invader). It is for these reasons that a recent study , published using data from the Boston Birth Cohort, has raised significant concern for pregnant women, since the potential lack of folate transport, as a result of high folic acid accumulation, could increase the risk of Autism Spectrum Disorders in children (ASD). Whilst it is not yet known if unprocessed folic acid does block the transport of folate into the brain, cerebral folate deficiency (CFD), a condition that occurs in some autistic children as a result of reduced folate transport, may be a risk of high folic acid intake. 
Thankfully, the food-state, fully natural form, folate is now available. Though it’s taking some time for the industry to catch up and reformulate products, Igennus and a few other supplement companies have already started transitioning to using various forms of folate. As one might expect however, not all folates are the same – the usual bioavailability considerations apply, like many nutrient forms. As always, we’ve deliberately selected what is currently the best and most bioavailable form of folate – known as Quatrefolic®. Despite the somewhat misleading name, it is the fully active version of folate, as ([6S]-5-methyltetrahydrofolate). Unlike synthetic folic acid, Quatrefolic® doesn’t require the activity of the dihydrofolate reductase enzyme and can enter the body’s cells and be used easily without any detrimental consequences, exactly as natural food sources of folate. A number of products are now available containing Quatrefolic, including Igennus Super B-Complex and MindCare supplements. Seeking out this form of folate would be wise for anyone supplementing with folate, not simply pregnant mothers.
Advice for pregnant women
It is important to remember that this recent study has not yet undergone peer review to be published in a scientific journal – the media headlines thus far were triggered by research presented at the 2016 International Meeting for Autism Research in Baltimore, USA. As a result, the quality of the research and validity of findings has not been confirmed. We would caution any women racing to change their supplement behaviours as it is well established that folic acid deficiency carries the risk of neural tube defects.
There are undoubtedly increasing safety concerns surrounding high intake of folic acid and, possibly, high B12 intake, due to the potentially damaging consequences of folic acid accumulation and reduced folate transport. As a result, women, and anyone else taking folic acid supplements, should establish their total daily intake from fortified foods and supplements and switch to lower doses of highly bioavailable, active folate forms like Quatrefolic®, as well as keeping an eye on vitamin B12 intake, prioritising the bioavailable methylcobalamin form to ensure they are getting the necessary nutrient levels for healthy babies, without any of the potential risks.
- Ramkripa Raghavan R, Fallin DM, Wang X. Maternal plasma folate, vitamin B12 levels and multivitamin supplementation during pregnancy and risk of Autism Spectrum Disorder in the Boston Birth Cohort. The FASEB Journal 30 no. 1 Supplement 151.6. April 2016
- Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA Cerebralfolate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013 Mar; 18(3):369-81.
- Sweeney MR, Staines A, Daly L, Traynor A, Daly S, Bailey SW, Alverson PB, Ayling JE, Scott JM: Persistent circulating unmetabolised folic acid in a setting of liberal voluntary folic acid fortification. Implications for further mandatory fortification? BMC public health 2009, 9:295.