<<<There is a high correlation between the sales of heavy coats in October and snow in December, but you would never ban the sale of those coats in order to prevent snow.>>>
Have you been expecting me to comment on the NIH report on Autism?
Here it is.
Bottom line, first:
This report cites a very good, scholarly article doing a “meta-analysis” of Tylenol and Autism and associated diseases, referred to as ASD (Autism Spectrum Disorder). A meta-analysis is a rigorous examination of a compendium of studies, grouped together and evaluated as a whole, and is, generally considered a great way to measure effects in a large population.
I will take some time to look at the data, but the point of this note is to look at the situation as a whole.
What is ASD?
Has there been an increase in cases due to an increase in disease, an increase in diagnosing the disease, an increase in the types of conditions included in the diagnosis, or some other factor?
If Tylenol creates an increased chance of developing ASD, what potential corollary effects may occur with the discontinuation of the use of Tylenol?
A new medication, an analog of folate, has been identified as having some promise for treating ASD; what is it, what does it do, and what are the potential side effects and benefits?
AUTISM
Autism was originally identified in 1911, but a 1943 study by Dr. Leo Kanner is generally considered to be the commencement of diagnosis. Kanner identified 2 factors. The first was a severe problem in social interaction from birth. The second was resistance to change/insistence on sameness.
In 1980 Autism was included in the DSM (Diagnostic and Statistics Manual) that serves as the official medical diagnosis catalog), but it wasn’t until 2013 that Autism was described as a multi-categorical system including multiple dimensions such as Autism, Aspergers, PDD (Pervasive Development Disorder), Rett’s Disorder and CDD (Childhood Disintegrative Disorder). This grouping was adopted by the WHO in 2018.
The first thing to understand here is that the diagnosis of Autism has expanded over the past 20 years. Whereas one subset of children would have been diagnosed as autistic in the early part of this century, multiple groups of children will be aggregated today. This drives the numbers of diagnosed autistic patients up.
At the same time, growing public awareness and increased recognition in public education settings have resulted in higher identification and diagnosis rates. As people become more familiar with the signs of Autism, it’s more likely that individuals who may have been missed in the past are now being identified.
So, it would be useful to look at diagnosed Autism rates since 2013. In 2014, there were 17 children diagnosed with Autism for every 1,000 children born, in 2014, that number has increased to 32. There seems to be a steady increase in Autism diagnoses, probably more so than might be explained only by increased awareness.
<<<Ice Cream sales increase in summer months. So do drownings. But, no, Ice Cream does not cause drowning.>>>
WHAT CAUSES AUTISM?
We simply don’t know. We don’t even know what physical, neurological, or metabolic changes result in Autism. A physician cannot look at a CT scan, an MRI, blood tests, or physical exam and determine that a patient is autistic. The diagnosis is behavioral.
And if we can’t describe the disease process, we can’t create animal of computer models for which we can simulate causes or treatments.
This is not terribly unusual. We don’t know what causes cells to lose their inhibition to divide and, thus develop into cancers. We don’t know what causes Type II Diabetes, or other metabolic disorders. 100 years ago, we had no idea about viruses and the diseases they caused. Medical research is a continuum, and we are only at one point on that discovery highway.
One explanation for the slow, but evident increase in rates of ASD could be an unidentified infectious agent with low transmissibility, meaning that infections are increasing, but at a very slow rate.
<<< There is an association between cold weather and colds. But it is not the cold weather that causes colds, it is viruses. People are more likely to be in close contact to others during cold weather, and this facilitates the spread of viruses, not the exposure to cold.>>>
THE DIFFERENCE BETWEEN CAUSE AND ASSOCIATION
To understand what is contained in the new study it is vitally important to understand the difference between finding a cause for a disease and finding an association between something and a disease.
For example, we know that we can isolate a virus from measles victims that is unique to that disease, is consistent from one exposed individual to another, and can cause the disease in animal models. The virus is the CAUSE of measles. Understanding the cause can allow for the development of treatments to either kill that virus or protect individuals from acquiring the virus (vaccines).
But, what if we were to look instead at the statistical prevalence of some other factor with the spread of measles. We might look at Mumps. We could do large studies of populations, and we would find that a large proportion of people that contract Measles had already contracted Mumps. That proportion might be statistically higher among Measles patients than people who did not have Measles. People with Measles have a much greater correlation with having had Mumps than those who haven’t had Measles.
Should we conclude that Mumps causes Measles? Of course not. The association of having had a Mumps infection with getting a Measles infection is not because Mumps causes Measles. We need to look under the data to try to understand the association. It could be that people who don’t get Measles vaccines also do not get Mumps vaccines. It could be that children who get Mumps and/or Measles spend more time in play groups and are more likely to spread viruses. It could be that a weakened system after a Mumps infection makes the child more susceptible to other viruses.
The important thing to understand is that a statistical association is not declaratory to a direct effect. Most associations are only “statistically relevant”; in other words, there is a larger chance of a particular result with the association, but that association may still be less than 50%.
<<< People think that sugar causes hyperactivity. Extensive research has found no causal linkage. The perception is more likely associated with the fact that children tend to consume more sugar at exciting events like birthday parties.>>>
TYLENOL ASSOCIATION WITH AUTISM
That brings us to the August study which looked at the potential association between Tylenol and Autism.
The review, authored by several researchers at Mount Sinai Hospital in NY, was published in Environmental Health, a well-regarded, peer-reviewed scientific journal. There should be no criticism of the source or the authors. This analysis, at least in my opinion, is a solid review of 46 previously published papers specifically looking at potential associations between Tylenol and Autism. Of the 46 studies, 27 showed a positive association, 9 showed no association, 4 showed negative associations. (The reason that 27+9+4 only equals 40, rather than 46, is because the group included studies on ADHD, ASD and NDD (Non-Development Disorders), and not all studies included all three groups.)
Notice that these studies were all investigating potential associations of Tylenol with Autism. They WERE NOT studies looking for ANY cause, they were specifically addressing Tylenol, and Tylenol only.
They were not looking at ALL pain/fever reducers and which might have a higher or lower associative relationship with ASD; they were ONLY looking at Tylenol.
They were not looking at papers comparing other dietary or environmental factors; they were ONLY looking at Tylenol.
The authors found that there is a statistically significant association with prenatal exposure to Tylenol with the eventual diagnosis of ASD. This is not a study designed to look for a CAUSE; it is a study of a potential ASSOCIATION of prenatal exposure to Tylenol resulting in an increased likelihood of developing ASD. And not all papers showed such an association. The majority of papers showed a statistically significant association.
Some fact to consider when evaluating this data.
One:
As stated above, Autism was identified in 1911 and formally diagnosed by 1943. Tylenol was not invented until 1950. Autism existed before Tylenol was created. In the best-case analysis, Tylenol DOES NOT cause Autism; however it may exacerbate the onset of the condition.
Two: Even as ASD diagnoses have increased in the last 10 years, Tylenol use has decreased.
Based on our understanding of association, we now have a clue about the development of Autism. But what should we conclude?
An association is not evidence of a cause.
Why would such an association exist?
There might be several potential explanations.
- Tylenol may exacerbate pre-existing conditions, increasing the likelihood that an individual might develop ASD.
- An overuse of Tylenol in some people due to chronic pain might cause some increase in ASD as above.
- The need to use Tylenol during pregnancy might indicate an increased susceptibility to viral infections during pregnancy, and those infections might trigger processes that result in ASD.
- The use of Tylenol might indicate an increased susceptibility to infections, and an infectious agent, currently undiscovered might result in ASD.
- The use of Tylenol may reflect a socio-economic difference in the groups of people who show an association with ASD, and this difference might indicate that these different groups have different exposures to other environmental toxins.
There are other potential explanations, and you may have your own. The point here is that the association may give researchers some new data to consider when investigating the causes of ASD, but it is not definitive.
WHY USE TYLENOL RATHER THAN OTHER FEVER REDUCERS?
Tylenol has become the go-to fever reducer and pain reducer in pregnancy and for infants and children. Why?
Standard Aspirin dosing for reducing fever or pain can result in a miscarriage, can result in congenital defects in the baby, can result in fetal kidney problems, late-term heart disease, and delivery complications. It is currently recommended that Aspirin be avoided during pregnancy.
NSAIDS like Advil and Aleve are also discouraged because there are well-documented risks to the baby including risks to lung development and heart development.
THE RISKS OF NOT TAKING TYLENOL DURING PREGNANCY
Then, why not avoid the risk of the association between Tylenol and ASD by avoiding the use of Tylenol, Aspirin, and NSAIDS during pregnancy?
There are additional risks raised if you avoid all of these medications. There are dangers associated with fever during pregnancy.
Untreated high fevers can result in heart defects, abdominal wall defects, oral clefts, or cleft palates. Interestingly, some studies have shown that increased fevers can also result in an increase in ASD.
FOLINIC ACID (LEUCOVORIN)
We well remember that during the COVID19 pandemic, fear and anxiety prompted many people to grasp at miracle cure-alls to combat the disease including Hydroxychloroquine, Ivermectin, Vitamin C, and others. These false hopes were generated by scientific articles that suggested positive effects and were, unfortunately, amplified by Talking Heads, politicians, and social media bloggers. But positive effects are not definitive results.
This week’s news has included a suggestion that Autism can be treated with a medication called Leucovorin; a medication commonly used to offset some of the side effects from methotrexate when used for chemotherapy.
Leucovorin is an analog (chemically similar to) folate, or Vitamin B9, which is important for brain development.
In some ASD patients, the immune system in the individual is making anti-self-antibodies that interfere with the uptake of folate in the brain, and Leucovorin may be able to work around this problem.
I have spoken in the past about how many diseases may have an underlying etiology (mechanism of disease) related to that person’s own immune system making antibodies that attack their own cells. This model would explain diseases like Diabetes, Rheumatoid Arthritis, MS, and Lupus. There are probably many more. And since each individual’s immune system is generated randomly, some people may have these antibodies, while others do not.
In ASD, more than 50% of patients show the presence of autoantibodies against the folate receptors in the brain, as opposed to less than 10% in the general population. It is possible that these autoimmune responses may cause ASD, and Leucovorin may be effective in overcoming this autoimmune response.
Recent clinical trials suggest that Leucovorin has shown significant improvements in language development. These results are statistically compelling, but not “curative”. For example, they have shown “increased” language improvement in 65% of the patients studied compared to 24% in the placebo group.
The importance of these studies is that they provide a viable pathway for future research.
Leucovorin is a very important step forward. But it is NOT a cure. It would be irresponsible to tell parents that there is now a cure for their child’s Autism. That is simply not true.