We all know that taking folic acid before and during early pregnancy helps prevent neural tube defects like spina bifida and anencephaly. But I for one was surprised to learn that taking folic acid may also help prevent autism.
Studies Linking Folic Acid Supplementation During Early Pregnancy with Autism Risk
In a population-based, prospective Norwegian Mother and Child Cohort Study of 85,176 mothers, women who took folic acid within the first 8 weeks of pregnancy had half the risk of having a child with autism: 0.10% versus 0.21%. Taking folic acid in mid-pregnancy, on the other hand, had no apparent impact on the risk of autism.
Because this was a cohort study, not a randomized controlled trial, we cannot say that folic acid caused a lower risk of autism.
For one, women who took folic acid supplements during early pregnancy had other traits associated with lower-risk pregnancies. They were more educated, more likely to be of normal weight, more likely to be first-time mothers, more likely to have planned their pregnancies, and so on.
In an attempt to rule out these alternative explanations, the researchers also looked at fish oil supplements during early pregnancy. Women who took fish oil supplements in early pregnancy were similar to those who supplemented with folic acid, yet taking fish oil was not related to the risk of autism.
The Norwegian Mother and Child Cohort Study is not the only study to find that folic acid supplementation during early pregnancy predicts a lower risk of autism. An earlier, smaller California-based study found that the higher levels of folic acid during the first month of pregnancy, the lower the risk of autism, with the lowest risk seen among pregnant women taking in 1000 μg or more per day.
Not at all studies have found a relationship, however. A 2015 Danish registry-based study found no effect of supplementation on the risk of autism.
The studies conducted to date are provocative but hardly definitive. We don’t know whether the relationship between folic acid and the development of autism is real, let alone causal.
So why do I take these findings seriously? Because the idea that not supplementing with folic acid can contribute to the risk of autism is both biologically plausible and supported by several indirect lines of evidence.
I’ll get into this evidence in a moment, but first let’s back up a second to briefly review what folic acid is and why it’s important during pregnancy.
What is Folic Acid?
Folic acid is a shelf-stable form of folate (vitamin B9), a water-soluble vitamin found in foods such as broccoli, chickpeas, lentils, beans, avocados, oranges, and fortified grains. Folate needs rise dramatically during pregnancy and can exceed the amount taken in from a normal diet. A lack of folate during very early pregnancy can lead to neural tube defects and other birth defects, so all major medical organizations currently recommend that women who are pregnant or who are planning to become pregnant take at least 400 μg of folic acid a day.
Why Would Folic Acid Affect The Risk of Autism?
First, let’s talk about biological plausibility. Is there a biological mechanism by which low levels of folate would raise the risk of autism? As it happens, yes.
Folate plays a key role in DNA methylation (the fixing of key genes to the “off” position) during early brain development. Failure to turn off specific genes could lead to the faulty wiring of neural circuitry that results in autism.
Second, do we have reason to believe that low folate levels during early pregnancy affect the risk of autism? Again the answer is yes.
Consider the anti-seizure drug valproic acid. Valproic acid interferes with the normal metabolism of folate and, when taken during pregnancy, is associated with a 3 to 5-fold increase in risk of autism.
Genetic variants can also affect how efficiently folate is metabolized. The C>T variant in MTHFR gene (5-methylenetetrahydrofolate reductase) lowers the efficiency of folate-driven DNA methylation. Women who carry one or more copies of the variant version appear to be overrepresented among mothers of autistic children, according to a recent meta-analysis.
(The MTHFR C>T variant certainly reduces the efficiency of folate-driven DNA methylation. But whether it also increases the risk of having an autistic child is controversial. Most of the studies to date have been poor quality, so we really need better research before drawing firm conclusions.)
(23andMe customers can check whether they carry the MTHFR C>T variant using the rs1801133 snp. Note that 23andMe reports the opposite strand. If you are AG or AA, you carry one or two copies of the less efficient version. This means you need a higher amounts of folic acid to achieve the normal physiological levels. Taking folic acid before conception and during early pregnancy is especially important for you.)
The Bottom Line
While the jury is still out on whether folic acid truly lowers the risk of autism, taking folic acid the month before conception and during early pregnancy is clearly a good idea. Early supplementation lowers the chances of a neural tube defect by 50-70%.
For pregnant women and women planning to become pregnant, the current recommended intake is 400-1000 μg per day. Either a multivitamin or a prenatal vitamin will cover this requirement. Most multivitamins contain 400 μg, while most prenatals contain 800 μg.
Women who have previously given birth to a baby with a neural tube defect, who have diabetes, or who are taking certain medications may need higher amounts of folic acid. (Here is a list of potential indications.) Most pregnant women will not need more folic acid than found in a standard prenatal vitamin.
References
Berry RJ, Crider KS, Yeargin-Allsopp M. Periconceptional folic acid and risk of autism spectrum disorders. JAMA. 2013 Feb 13;309(6):611-3. doi: 10.1001/jama.2013.198.
Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013 Apr 24;309(16):1696-703. doi: 10.1001/jama.2013.2270.
James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, Cutler P, Bock K, Boris M, Bradstreet JJ, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet 2006;141B:947–56.
Pu D, Shen Y, Wu J. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism Res. 2013 Oct;6(5):384-92. doi: 10.1002/aur.1300. Epub 2013 May 7.
Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J. Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol. 1996 Jun 24;370(2):247-61.
Steenweg-de Graaff J, Ghassabian A, Jaddoe VW, Tiemeier H, Roza SJ. Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study. Eur J Public Health. 2015 Jun;25(3):431-3. doi: 10.1093/eurpub/cku126. Epub 2014 Jul 31.
Surén P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, Lie KK, Lipkin WI, Magnus P, Reichborn-Kjennerud T, Schjølberg S, Davey Smith G, Øyen AS, Susser E, Stoltenberg C. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013 Feb 13;309(6):570-7. doi: 10.1001/jama.2012.155925.
Surén P, Susser E, Stoltenberg C. Maternal folic acid supplementation and risk of autism–reply. JAMA. 2013 Jun 5;309(21):2208. doi: 10.1001/jama.2013.4879.
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Vahabzadeh A, McDougle CJ. Maternal folic acid supplementation and risk of autism. JAMA. 2013 Jun 5;309(21):2208. doi: 10.1001/jama.2013.4876.
Virk J, Liew Z, Olsen J, Nohr EA, Catov JM, Ritz B. Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders. Autism. 2015 Sep 25. pii: 1362361315604076.
Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology. 1992 Apr;42(4 Suppl 5):17-24.
no way
Thank you for this piece. I’m wondering if you’ve ever done research on prenatal vitamins / supplements in general. I’m concerned that, with the now widely accepted view that most people would be better off getting their nutrients from food, prenatals may be overkill. For example, many contain retinyl palmitate (synthetic vitamin A) which, in high doses, has been linked to birth defects. Aside from folic acid, iron and in some cases Vitamin D, what is really necessary for a pregnant woman with a healthy diet?
I’m enjoying your science blog more than Enily Oster’s book or columns, but I take issue with this post. Folic acid as presented in a supplement is not presented in a way that is readily available for the body to use. Folic acid is best used when gotten from real food, and it’s quite easy to accomplish this. Furthermore, when presented in a multivitamin (which prenatal vitamins are), it doesn’t come alone and the formulas for vitamins vary greatly as do their effectiveness. It’s so easy to say, “take a supplement,” but it’s not really the truth of the science.
interesting! Do you know of some good sources on this?
I’ve read that it is safer and more effective to get this supplement through folate (natural) rather than folic acid (synthetic) and that there is some indication that taking it in high enough doses prior to conception may also lower the risk of ovulating eggs with the extra chromosome found in Down Syndrome.
I faithfully took a prenatal vitamin pre and post conception (usually they have 8 mg vs the 4 mg in a regular women’s vitamin) with all of my boys and the oldest one has high functioning autism. Among support groups I have joined, there is a strong belief that autism is a normal variation and runs in families, with it not being uncommon for parents seeking support related to their affected child to later recognize a higher functioning type of autism either in their self or their partner. Anecdotally, there does appear to be a strong representation of parents and children with autism that have the MTHFR mutation and other gut problems.
I guess now I know if I decide to try for another pregnancy I now know of one more reason to push the folate both pre and post conception.
Just came across this: https://www.statnews.com/2016/05/11/autism-folic-acid-pregnancy/ which indicates too high levels of folic acid in a mother’s blood is associated with an increased risk of autism. This, of course, could be caused by certain people having trouble metabolizing folic acid, rather than just the levels of the vitamin they have been taking. I have also come across articles discussing excessive levels of folic acid in the blood being associated with the growth of certain kinds of cancer, leading to an upper limitation recommendation of no more than 1000mcg. However, interestingly enough, there is no upper limitation recommendation for folate. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/ The science is still confusing, but this suggests to me that if moms want to get more folate, they should get it in the form of folate supplements or folate rich foods rather than from increasing supplementation with folic acid.