A recent study  publishing data from the Boston Birth Cohort has resulted in some alarmist headlines and raised a number of significant concerns over the use of folic acid in pregnancy. The media reporting suggests that excessive intake of folic acid, and more so when combined with vitamin B12, can increase the risk of developing Autism Spectrum Disorders (ASD). Here’s what you need to know to make folate supplementation safe and why you shouldn’t panic.
Why folic acid has been linked to ASD
Folate supplementation is an established nutritional requirement during pregnancy, necessary to reduce the risk of developing neural tube defects that can lead to conditions such as spina bifida. Whilst folate refers to the various tetrahydrofolate derivatives naturally found in food, folic acid refers to the oxidised synthetic compound used in dietary supplements and food fortification. Unlike natural folates (which are metabolised to tetrahydrofolate in the mucosa of the small intestine and are able to enter the folate cycle), folic acid undergoes initial reduction and methylation in the liver, where conversion to tetrahydrofolate requires the action of the enzyme dihydrofolate reductase. The low activity of this enzyme in the liver, combined with a high intake of folic acid, can result in unnaturally high levels of unmetabolised folic acid (UMFA). Even with intakes as low as 200ug of folic acid, the dihydrofolate reductase enzyme can become saturated, allowing UMFA to pass into the bloodstream by passive diffusion. It is unknown if UMFA could block the transport of folate into the brain or pass into the brain itself, but cerebral folate deficiency (CFD), a condition among some autistic children, occurs when auto-antibodies to the folate receptor prevent folate from entering the brain. These auto-antibodies act to prevent folate transfer to the brain with potential neurological consequences.
What did the researchers study?
The purpose of the reported study was to investigate the role of preconception/prenatal nutrition in the development of Autism Spectrum Disorder (ASD). A total of 107 children from 1,391 mothers recruited between 1998 and 2013 were diagnosed with ASD. Although maternal multivitamin supplementation (3–5 times/wk) was associated with significantly lower risk of a diagnosis of ASD, 10% of mothers were found to have folate in excess of 59nmol/L, doubling the risk of ASD (HR: 2.27; p=0.007), and 6% of mothers had vitamin B12 levels in excess of 600 pmol/L, tripling the risk (HR: 3.01; p=0.001). Alarmingly, having excessive levels of both nutrients boosted the risk of children developing ASD by 17.6 times (HR: 17.56; p<0.001) and the authors suggest that mothers with higher levels may simply have consumed too much folic acid-fortified food or taken too many supplements.
Why we should be using body-ready Quatrefolic ([6S]-5-MTF)
Using highly bioavailable, pre-methylated forms of folate, such as the novel folate source Quatrefolic®, in place of folic acid, overcomes all issues associated with folic acid and the potential build-up of UMFA in biochemical pathways. Unlike synthetic folic acid, folate ([6S]-5-methyltetrahydrofolate – or Quatrefolic) is pre-methylated and does not require the activity of dihydrofolate reductase, allowing it to enter the folate cycle with no detrimental consequences. Sourcing products containing Quatrefolic, which is also significantly more shelf-stable than other forms of supplemental folate, should be a key priority for anyone needing to increase their folate intake.
Another premature headline?
Whilst the group presented their findings at the 2016 International Meeting for Autism Research in Baltimore, USA, their work has not undergone the standard peer review process and has faced high levels of backlash for creating alarm among pregnant women, which may encourage changing behaviours related to folate intake or supplementation, resulting in possible higher risk of neural tube defects for the foetus. Whilst there are undoubtedly increasing safety concerns surrounding high intake of folic acid due to the presence of UMFA , more focus should be placed on choosing supplements containing Quatrefolic, the pre-methylated folate ([6S]-5-methyltetrahydrofolate.
- 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.