Wednesday, September 22, 2010

Folic Acid Increases the Risk of Autism aka the Dangers of Bad Data

As I talked about last time, another study on thimerosal was released last week.  Like some of the studies before it, this one found that not only was thimerosal not involved in causing autism but also that a higher exposure actually lowered the the odds of having autism.  Or in other words, being injected with a higher level of mercury actually greatly decreased your chances of having autism.

If that result seems a bit strange to you, you are not alone.  I don't think that many people would claim that this is actually a valid finding (although there are some) and the researchers acknowledged as much when they said that they "are not aware of a biological mechanism that would lead to this result."  Although, to be slightly glib, it would be one of the great ironies in recent history if thimerosal actually did actually protect against autism.

But still, the result reached statistical significance which means that it is unlikely to have happened by chance, and this isn't some fly by night paper were the statistics were in doubt.  The data in this paper was the result of a seven year effort and the published paper and supplemental material reaches almost 400 pages.

I think the answer to the puzzle is pretty obvious here and I am going to use another significant finding from the study to illustrate the point.  Buried on page 164 of Volume I of the supplemental material is the following statement -

"Use of prenatal vitamins containing folic acid was associated with a higher odds ratio of ASD"

This is also a statistically significant relationship.  If you look on page 169 of the volume, you will see that, if the mother took prenatal vitamins while pregnant, her children were more than twice as likely to have autism.  This result is based on the data that 96% of the mothers of children who have autism took folic acid while only 91% of the mothers of "typical" children did.  When you put these numbers into the models with the rest of the data - the same models used to determine the main no relationship result - out pops this strange relationship.

For those of you who don't know, folic acid is essential to many bodily functions, is used to help synthesize and repair DNA, and helps determine which parts of the generic material is active.  Pregnant women have been taking folic acid during pregnancy since at least 1993 because it can mostly prevent neural tube defects such as spina bifida.

Here we have yet another improbable result from this study.  So, what could be going on?

When you consider the facts that folic acid plays a role in maintaining and repairing genetic code and that autism seems to littered with many rare genetic mutations, it might be possible that taking too much folic acid during pregnancy could increase the chances of a child having autism.  However, even though the timing (1993 onwards) might agree with rising autism rates and there might be some kind-of plausible mechanism for the relationship, I don't think that this is likely.

Which leads to another possibility.  I am sure that most of you have heard the oft-repeated phrase about how correlation does not imply causation - this would be a classic example of it.  It is possible that folic acid use is highly related to another factor and it is this other factor that is causing autism.  If I had to guess, folic acid use during pregnancy could be be correlated with affluence.  Meaning that mothers who are more well-off are more likely to wait until later in life to have children and are more likely to do the "right" things during pregnancy - such as take folic acid.  But it is equally likely that this relationship could be flipped and affluence, which has been linked elsewhere to a higher risk of autism, is the dependant factor and it folic acid use that is the causative factor.  That is the problem with these sorts of relatinships, you are never quite sure what is a cause and what is simply along for the ride.

Another explanation would be that the association would happen by simple dumb luck.  Even with all of the robust methodologies and fancy statistics that researchers use, it is still possible for a significant result to appear that is due to simple random chance.  This is why it is very important that all scientific findings be replicated by other researchers using a different set of data.  The fact that thimerosal is actually protective has been suggested by other studies but I am not aware of any others finding a relationship with folic acid use.

Regardless, I think the most likely explanation for what is going on is the simplest - there is a problem with the study's data.  I would have to say that a problem with the underlying data is one of the most overlooked and under-considered problems out there.  If the data that the analysis and conclusions of the study are based on is biased or does not properly represent what you trying to study, everything that the data is based on is flawed.

Since this study found that a higher exposure to thimerosal decreases the chance of autism and that taking folic acid during pregnancy raises the chance of autism, I think it is safe to say that something is not quite right with the data in this study.

As the saying goes - garbage in, garbage out.


  1. HI MJ -

    I'm not at all convinced that the folic acid data is artifact. I actually kind of like it as far as a contributory factor.

    We've been supplementing all of our wheat up and above the prenatal vitamins in a successfull effort to ward off spina bifida. The formative timeframe of harm in spina bifida is the first trimester, but (most) pregnant women keep on firing with folic acid until their child is born.

    So what? It turns out, folate is being shown to be a powerful epigentic regulator; essentially something that can affect how lots of genes operate. For example,

    Periconceptional Maternal Folic Acid Use of 400 µg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child

    BACKGROUND: Countries worldwide recommend women planning pregnancy to use daily 400 microg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight.

    Like a great number of things, here we are nearly two decades after initiating a national health policy without an understanding of the underlying mechanisms of action. Sound familiar?

    METHODOLOGY/PRINCIPAL FINDINGS: IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (-1.7% methylation per SD birthweight; p = 0.034).

    CONCLUSIONS: Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use.

    I do not believe for a single second that we understand the implications of this type of modification. Note that this paper was published in 2009. (!)

    We do have a growing body of studies on epigenetics and associated genetic expression in the autism realm. I'm not saying folic acid is the only way to get there, but it certainly does appear to be one way.

    - pD

  2. Hi pD,

    I partially with you about folic acid. It is easy to look at what it role it plays in the body and how little we understand about how it works and see a plausible mechanism.

    It is also tempting because here we have a substance whose use has been increasing during the same time that the rates of autism have been going up. You can even use it to explain away some strange facts about autism such the rate of autism increasing with socioeconomic status.

    And as a bonus, it would also explain why identical twins don't always both have autism or have the same severity as well as the disconnect between the rates in fraternal twins and ordinary siblings.

    And, if I am not mistaken, the main biological pathway that folic acid influences has been shown to be disrupted in children with autism?

    I don't know whether too much prenatal exposure to folic acid could force this pathway to function less than optimally but it would certainly be worth looking at


    In this study, the rates of folic acid use in both the case and control groups were very high, 96% in the case, 91% in control. And yet the odds ratio was over 2.0 which seems strange to me.

    How can you say that taking folic acid doubles your chances of autism based on a subgroup of less than 9% of your study population? If you look at the numbers, about 932 of the children had prenatal exposure to folic acid while the remaining 86 did not.

    Given the massive skew towards the exposure group and the out-sized odds, I would think that the relationship was a statistical fluke or some sort of bias in the data. Especially when you consider that the same data showed that higher thimerosal exposure seems to protect against autism (another unlikely result).

    But who knows, I could very easily be wrong and I would agree that the issue needs some follow up.

  3. Folic acid is an antagonist of the GABA(A) receptor. It's actually a fairly 'unnatural' substance. The natural vitamin, found in food, is folate. Folic acid needs to be converted to folate in the body by the enzyme, dihydrofolate reductase. The efficiency of the conversion process is highly variable between individuals, with a fivefold difference between the most and least efficient converters (PMID: 19706381).

    Folate also acts as an antagonist at the GABA(A) receptor, but folic acid has a more powerful antagonistic action (PMID: 2166659). Other chemicals which have been associated with autism are insecticides (PMID: 17938740), phthalates (PMID: 19822263) and methyl mercury (16914205). All are GABA(A) receptor antagonists. This is unlikely to be coincidence.

    If GABA transmission in the developing brain is hindered by GABA(A) receptor antagonists, it is reasonable to assume that those receptors may become more sensitive and/or numerous to compensate for this. Babies will therefore be born with GABAergic neurons which are hyperfunctional.

    I believe this is responsible for the modern 'epidemics' of autism, ADHD, asthma and type 1 diabetes, although the mechanisms which are responsible are complex, involving chronic, aberrant sctivation of the immune system. I have written about this on my blog at -

  4. Sorry, I should have added that a much condensed version of the blog can be seen at the Environmental Illness Resource website titled 'Immune Mimicry Disease: Theory and Implications for Autism and ADHD'

  5. I am not surprised about this study. Spend some time researching MTHFR and autism.

    Here is an interesting study about folate and autism prevalence:

    Here are some links about the MTHFR/autism connection

  6. I am not buying it because i don't think some of the info is truee