Autism Regression: A prevalence study

A review of: Baird, G., Charman, T., Pickles, A., Chandler, S., Loucas, T., Meldrum, D., Carcani-Rathwell, I., Serkana, D., Simonoff, E. (2008). Regression, Developmental Trajectory and Associated Problems in Disorders in the Autism Spectrum: The SNAP Study. Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-008-0571-9

Although most children with autism present very early signs and symptoms and a linear developmental trajectory, a small subset of children present a trajectory characterized by normal development followed by a loss of acquired skills or a failure to use the acquired skills. This pattern has been termed autistic regression. Possible explainations for this phenomenom have varied from a genetic effect on brain restructuring and pruning during the early stages of life, to enterocolitis due to vaccinations, to epilepsy. In this study, the authors explored differences in developmental outcomes for children with and without regressive autism, and the association between regression and enterocolitis and epilepsy. This study examined a population cohort born in the UK in 1990 and 1991. Out of 56,946 children in this cohort, 218 had and ASD diagnosis by age 10. A subset of these children were evaluated via ADOS and ADI and divided into a broad autism (N=105), narrow autism (N=53), and no autism (N=97). The narrow autism group met full criteria for autism based on ICD-10. The broad autism group met clinical consensus for autism but not full ICD-10 criteria. These children were then evaluated for history of epilepsy, gastroinstestinal problems, and developmental regression. 39% of children with narrow autism had a history of regression during development. This compared to 11% of children with broad autism, and 3% of children with no autism. On average this regression occurred around the 25 month of age. There were no differences in IQ or adaptive functioning between those with or without regression. However, those with regression classified in the broad autism group had significantly more symptoms than those without regression also classified in the broad autism group. Regression was not associated with gastroinstestinal symptoms or with epilepsy.

Acetaminophen use and Autism.

A review of: Schultz, S.T., Klonoff-Cohen, H.S., Wingard, D.L., Akshoomoff, N.A., Macera, C.A., Ming Ji, . (2008). Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: The results of a parent survey. Autism, 12(3), 293-307. DOI: 10.1177/1362361307089518

A study in the latest issue of the journal Autism examined the possible role of acetaminophen use after MMR vaccine and autism. The authors provided an excellent review of the MMR vaccine-autism research, which indicates that although some clinical studies have found a link, most epidemiological studies have failed to find an association between MMR and autism. The authors noted that acetaminophen is commonly used to treat the adverse reaction of MMR vaccinations such a fever and rash. In addition, one study (Alberti et al, 1999) showed that some low functioning children with autism process acetaminophen differently. Thus, the authors proposed a innovative hypothesis: Does acetaminophen use after MMR vaccination increase the risk for Autism?

The authors recruited parents of typically developing children and children with autism via internet advertisement. The total sample included 83 parents completing the survey for children with autism and 80 parents completing the control survey. The surveys included a variety of questions about the child such as age, gender, what medications were used to prevent or treat reactions to the MMR vaccine, including aspirin, acetaminophen, or ibuprofen. The survey of parents of children with autism included additional questions about their children diagnosis such as whether a regression in development was observed.

The authors found that parents of children with autism reported:
- more adverse effects of MMR vaccine, including fever, diarrhea, irritability
- increased presence of concurrent illnesses with MMR vaccine
- more acetaminophen use after the MMR vaccine among children who had a reaction to the vaccine, children who had a regression in development, and those under 5.
- more acetaminophen use between 12 and 18 months of age
No association was found between ibuprofen use and autism.


A few caveats:
The finding that parents of children with autism reported more adverse effects of MMR vaccine or more concurrent illnesses with MMR vaccine is not overly informative. Note that these results were based on parental reports via internet with no possibility of verification of accuracy of such reports. So it is completely plausible to argue that given the extended media coverage of the vaccine-autism link, some parents of children with autism are more attuned to their children histories after vaccination and thus are more likely to remember or report complications. What is informative and actually interesting is that there was a significant difference in reports of acetaminophen use as compared to ibuprofen use. This difference can not easily be explained on the basis of some report bias. The problem is that acetaminophen use was reported much more frequently than ibuprofen use by all parents. So it could be argued that since parents of children with autism were more likely to report complications (even if just a by-product of recall bias), the use of acetaminophen will also appear to be different between the two groups.

Mercury Exposure and Autism: Should you check for nearby power plants?

...But this study is compelling in showing an association between mercury exposure and autism rates, and scientists can not just ignore it under the basis of its imperfect design and inability to make causal links – if that is the case, then only carefully controlled laboratory studies, with poor external validity, should be published and accepted as contributors to our greater scientific knowledge.

A review of: PALMER, R., BLANCHARD, S., WOOD, R. (2008). Proximity to point sources of environmental mercury release as a predictor of autism prevalence. Health & Place DOI: 10.1016/j.healthplace.2008.02.001

This fascinating, yet bound to be controversial, study hit the news yesterday as it was made available (pre-publication) by the Journal Health & Place. The study is simple, straightforward, elegant, with some powerful findings. In fact, the findings are somewhat daunting given the simplicity of the design. The researchers reviewed the amount of mercury release reported by industrial facilities and power plants in the State of Texas in 1997 from data provided by US Environmental Protection Agency Toxics Release Inventory. They compared these data against autism rates in 1997 and 2002 as measured by schools' autism classifications provided by the Texas Education Agency. Using a specialized geographical analysis system, the authors were able to locate each source of mercury and calculate the distance between each mercury source and each school. The results:

Industrial release of mercury and distance to industrial sources independently predicted increased rates of autism. The association with industrial release of mercury was not linear, instead the statistical model fit suggested an accelerated risk. This association remained statistically significant after controlling for specific variables such as SES, urbanicity, and race.

Power plant release of mercury and distance to power plant independently predicted increased rates of autism. In this case the association was linear (not accelerated). Again, this association remained statistically significant after controlling for other variables.

It is easy to dismiss these findings as inconsequential because they are ‘correlational’ in nature, or do not really prove anything. Researchers are too often guilty of selective acceptance of research: those studies that fit the consensus are accepted while those that don’t are dismissed for their methodological flaws – even though the studies we accept are equally flawed.

In the spirit of fairness I have to say that these findings are strong. Their methodology and analytical process are not any different from what is commonly seen in social science or epidemiology research. Is it perfect? Far from it. Is it useful or informative? Definitively! The data speak very clearly: In Texas, mercury release from industrial sources and power plants in 1997, and school proximity to these sources, are associated with rates of autism in 2002 as measured by school special education classifications.

Does this mean that mercury causes autism? Not at all. In the last sentence of the previous paragraph you can not replace the words are associated with with the word cause. There is a major difference. The data, albeit strong, have limitations. For example, the most obvious (to me) alternative explanation is that mercury release and proximity to these sources is also associated with another mystery factor that is causing this apparent association and that in fact, mercury release has nothing to do with autism rates in 2002. Let’s hypothesize that these power plants and industrial sources also release another toxin – let’s call this toxin autisimic (this is a made up toxin). These sources release mercury and autisimic at the same rate, so for each pound of mercury released there is a pound of autisimic released. It is possible then that this autisimic toxin directly increases the risk for autism, and this could explain completely the strong (but now obviously inaccurate) association between mercury release and autism.

Does this study show that vaccines cause autism? Absolutely not. I know this question may sound ludicrous to some, but I pose it rhetorically because I am certain that some will make the wide leap and link these findings to the vaccine issue.

There are other problems and limitations with this study, such as how autism rates were calculated (using all children instead of only those born inor after 1997), whether the autism rates are truly climbing and not explained by other factors, whether there are other variables that could be explaining this relation, etc, etc --- and yes, this study does not prove or directly indicate that autism is caused by mercury exposure (click here for a much more critical review of this study). But this study is compelling in showing an association between mercury exposure and autism rates, and scientists can not just ignore it under the basis of its imperfect design and inability to make causal links – if that is the case, then only carefully controlled laboratory studies, with poor external validity, should be published and accepted as contributors to our greater scientific knowledge. This is study is far, far, from perfect, and many changes should have been requested prior to publication, but I can say the same of 90% of what is published today.

A micro history of the recent mercury autism controversy.

A commentary on: Aschner, M. (2008). Response to Article by DeSoto and Hitlan on the Rlationship Between Mercury Exposure and Autism. Journal of Child Neurology, 23(4), 463-463. DOI: 10.1177/0883073808314647

DeSoto, M.C., Hitlan, R.T. (2008). Concerning Blood Mercury Levels and Autism: A Need to Clarify. Journal of Child Neurology, 23(4), 463-465. DOI: 10.1177/0883073808314718

The latest issue of the Journal of Child Neurology includes two letters regarding the mercury-autism controversy. For most people familiar with this issue, this summary will not present anything new, but for those interested in knowing the basics of this latest controversy, here is a micro-crash course on the mercury-autism link.

In 2004 authors Ip, Wong, HO, Lee, and Wong, published an article in the Journal of Child Neurology comparing the blood and hair mercury levels of children with and without autism in order to examine if a mercury-autism link existed. The results were as follow:

There was no difference in the mean mercury levels [between the group]. The mean blood mercury levels of the autistic and control groups were 19.53 and 17.68 nmol/L, respectively (P = .15), and the mean hair mercury levels of the autistic and control groups were 2.26 and 2.07 ppm, respectively (P = .79).

The conclusion, which was supposedly inconsistent with the theory that mercury causes autism, shocked some members of the autism community. I said ‘supposedly’ because whether or not the mercury theory is correct, the manner in which the results are presented goes beyond what the data can actually say. Specifically, the authors concluded that:

Thus, the results from our cohort study with similar environmental mercury exposure indicate that there is no causal relationship between mercury as an environmental neurotoxin and autism.

The problem here is that this data only speak to concurrent levels of mercury and autism diagnosis. So it is entirely possible that in some children pre- or post-natal exposure to this toxin results in neurodevelopmental changes leading to autism symptoms. This idea does not imply that mercury levels would remain high in affected children. It only implies that that these children were exposed to this toxin. A similar example would be exposure to alcohol during pregnancy leading to fetal alcohol syndrome (FAS). Children with FAS do not have higher levels of alcohol in their blood than typically developing kids. I am not endorsing the mercury theory, but I am stating that the conclusions as stated by Ip go beyond what their data say.

But back to the Ip et al. (2004) study. In 2007, DeSoto and Hitlan published an article in the Journal of Child Neurology after they found a major mathematical mistake in the original findings reported by Ip. Specifically, they found that the non-significant differences in blood levels reported by Ip was an error and significant differences were actually observed. I did the calculations myself, and yes in fact, the kids with autism had significantly higher mercury levels than the control group (t = 2.6163; df = 135; p>.01).

Then in the latest issue of the Journal of Child Neurology, Dr. Michael Aschner published the following short correspondence:

In a recent article DeSoto and Hitlan1 reanalyzed an original data set, concluding that a relationship exists between blood mercury levels and the diagnosis of autism spectrum disorder (ASD). The conclusion is based on the reanalysis of hair to blood mercury ratios. Hair to mercury concentration ratios while informative need to be considered within the context of a temporal relationship. As elegantly demonstrated by Grandjean and colleagues, mercury levels in the hair reflect a delayed average compared to the blood mercury level averages. That is, mercury hair concentrations at hypothetical time point T reflect blood mercury levels at T minus 1 to 2 months. Chelation therapy and changes in diet and fish consumption (both more likely to occur in the ASD group) in the 2 months preceding the mercury analysis are likely to affect blood, but not hair mercury sample concentrations. The analysis by DeSoto and Hitlan, which presumes that the 2 biomarkers are equally affected, is clearly erroneous. Thus, absent appropriate corrections for the temporal fluctuations in mercury levels, the conclusions should be interpreted with utmost caution and revalidated taking the above issue into account.

This was followed by a response from DeSoto and Hitlan explaining further that their 2007 study addressed directly the error in blood sample Mean differences as reported by Ip et al in 2004. DeSoto and Hitlan re-analyzed Ip's data showing that in fact blood mercury levels in the autistic group were higher than in the control group. This finding, and the original Ip error, had nothing to do with hair-to-blood ratios as described by Dr. Aschner. Dr. Aschner criticism is much more applicable to a separate hair analysis performed by DeSoto and Hitlan showing that the autism group had lower hair mercury levels than expected based on their blood samples, which is inconsistent with the idea that chelation therapy may have affected the blood levels. I explain: blood levels reflect immediate levels of mercury while hair levels reflect levels 1 to 2 month prior to testing. Thus, if blood levels at Time 1 were 20 (I’m using random numbers as example), then hair levels at Time 2 (2 month later) should be 20. If after Time 1 the child undergoes chelation therapy, then theoretically, blood levels at time 2 (2 month later) should be lower than 20 but hair levels should remain 20. Thus at Time 2, blood levels should be lower than hair levels. This was not supported by DeSotos’ analyses. What does this mean? Simply that the differences in blood levels found between the autism and control group are unlikely to have been affected by chelation therapy in the autistic group since the hair-blood analysis was not consistent with what is expected if chelation therapy had occur. WARNING: this is not a statement supporting chelation therapy, it is just a clarification of a possible interpretation of this data.

Does this mean that vaccines cause autism? Not at all. Again, although we would like to think that data can give us the entire story, data speak in morphemes rather than words, or sentences. This data only indicate that this particular group of children with autism had higher mercury levels than typically developing children. This could mean many things, such as that the children with autism have difficulty processing mercury or that the children with autism were exposed to higher levels of mercury, and these explanations in turn, may or may not have anything to do with the symptoms observed in children with autism, both in terms of symptom presentation, severity, or causes. These data simply do not give us that information.

More recent articles about the Autism and Mercury controversy and the Autism and Vaccines controversy can be found here.

Autism in South America. How does it compare?

A review of: Montiel-Nava, C., Pena, J.A. (2008). Epidemiological findings of pervasive developmental disorders in a Venezuelan study. Autism, 12(2), 191-202. DOI: 10.1177/1362361307086663

I decided to write a brief review of this article for two reasons. First, I often hear questions about how the rate of autism in the US, Canada, and the UK compare to that found in other countries. The answer to this question is relevant, although not as illuminating as most would like, to the major scientific debates regarding the perceived increase in rate in autism during the last two decades and the role of specific environmental factors in the development of autism. The second reason is more personal. Once upon a time, when Michael Jackson was on top of the charts, I called Venezuela my home.

The authors examined the rates of autism in a large metropolitan area of Venezuela, a country of 26,000,000 people with a large youth population (33% under the age of 14). In the first step of the study, the authors reviewed local medical records to identify children with a diagnosis of ASDs. The authors found 610 current cases in children between 3-9 years of age. Then, the authors independently confirmed the diagnosis in about 70% of the sample (N=430). The remaining children did not meet standard DSM-IV criteria or there was insufficient information to achieve an adequate diagnosis. This resulted in a prevalence rate of 1.7 per 1,000. Although this is much lower than reports in the US and other industrialized countries, the authors stated that unlike some previous reports, their methods provided rates for documented (identified) cases and did not include estimations of children that may be affected but have not yet been identified. In addition, the authors used only administrative sources for case identification (medical records) instead of large scale direct community assessments. Reliance on only administrative sources has been shown to provide lower prevalence rates. In summary, the rates of autism in Venezuela appear to be much lower than in other industrialized countries. However, the specific methods used in this study may have affected the results; in addition to the more common explanations, such as more limited access to specialized services, limited awareness about autism in the population, and higher stigma associated with these disorders, all of which limit service-utilization in developing countries.

A final note: I was informed by two Venezuelan MDs that thimerosal was still routinely used in vaccines in Venezuela. However, I sent a request for clarification to the pediatricians' organization in Venezuela and a governmental health official, since I was not able to confirm this information from any reliable online source.

Autism and Mercury: The Pediatrics thimerosal study

Title: Mercury Levels in Newborns and Infants After Receipt of Thimerosal-Containing Vaccines
Authors: Michael E. Pichichero, MDa, Angela Gentile, MDb, Norberto Giglio, MDb, Veronica Umido, MDb, Thomas Clarkson, PhDc, Elsa Cernichiari, MSc, Grazyna Zareba, PhDc, Carlos Gotelli, PhDd, Mariano Gotelli, PhDd, Lihan Yan, MSe and John Treanor, MDa
Source: PEDIATRICS Vol. 121 No. 2 February 2008, pp. e208-e214

The famous Thimerosal study from the American Academy of Pediatrics journal finally was released this morning. This short review could not possibly do justice to the major controversy about mercury and autism, so I will limit the commentary to the results of THIS STUDY ONLY. Given that Thimerosal is commonly used in vaccines in other countries outside of the US and Europe, the researchers teamed with a research group in Argentina to examine how infants and toddlers process Thimerosal when injected as part of their standard vaccination procedures. The researchers examined newborns, 2 month old babies, and 6 month old babies. The infants received a birth dosage of BCG and HBV vaccines that contained 32.5 ug of mercury (ethyl mercury). The 2-months-olds received the first dosage of diphtheria-tetanus-whole-cell pertusis and Hib, the first dosage of polio, and the second dosage of HBV, providing a total of about 40-50 ug of mercury. Finally the 6-month-olds received the additional dosage of diphtheria-tetanus-whole-cell pertusis, Hib, and HBV for a total mercury intake also between 40-50 ug. Then the researchers examined mercury levels in the blood, stool, and urine 1, 3, 5, 11, 21, and 30 days after the vaccinations. The 1/2 life of mercury was found to be 3.7 days in new born, 2 days for 2-month olds, and 2.2 days for 6-months olds. Blood mercury levels returned to baseline by day 11 after the vaccination. The 1/2 life refers to the time it takes for the drug to reach 1/2 of its original value (max in the first cycle). Why is this significant? Because part of the argument against the use of Thimerosal in vaccines was based on the effect of Methylmercury in adults. Methylmercury has a 1/2 life of about 50 Days with studies reporting as long as 180 days! This long 1/2 life of Methylmercury means that the person is exposed to levels of mercury for extended periods of times (weeks), which has many potential side effects. The argument made by the authors of this study is that the 1/2 life of Ethyl Mercury as found in children is only about 3 days, significantly reducing the exposure to mercury in these babies. Now, the authors correctly state that this study does not address the "toxicity" of thimerosal, so it could be argued that exposure to ethyl mercury even for a short period of time (3-4 days)could be enough to cause maturational changes in the brain leading to permanent impairments.

Autism and Vaccines: The California Thimerosal Study

Title: Continuing Increases in Autism Reported
to California’s Developmental Services System
Authors: Robert Schechter, MD, MSc; Judith K. Grether, PhD
Source: Arch Gen Psychiatry. 2008;65(1):19-24

While we wait for the release of the new Academy of Pediatrics study on Thimerosal (see last blog entry), I thought this recent article from the Archives of General Psychiatry was worth reviewing, especially given the current controversy regarding ABC “Eli Stone” episode. This study was simple and elegant. It follows a straightforward logic. If the use of Thimerosal in vaccines has a causal role in the development of autism, the elimination of Thimerosal in vaccines should result in a drop in the rates of autism, or at the very least, a pause in the accelerated increase of these rates. To test this hypothesis the authors reviewed the rates of autism in the State of California from 1995 to 2007. The found a consistent increase in rates during these 11 years without any indication of a slowdown or a drop in autism rates. One particular finding is worth mentioning. The rates of autism in 3 to 5 year old kids increased from 3 to 4.1 per 1000 live births from 2004 to 2007, which represented a higher increase than those observed for all other developmental disabilities. This is of major importance because during this same period all but trace amounts of Thimerosal had been eliminated from vaccines in the State of California. If the link between Thimerosal and autism were "causal" and strong, the rates of autism during the 2004-2007 year should have dropped. Instead these rates increased. Now, although strong, this is far from conclusive evidence, since people could argue that rates continued to increase because of vaccinated babies moving to California or that such trace amounts of Thimerosal were enough to continue the increase in autism. But this last hypothesis will likely be answered by the Pediatrics article due to come out next week.

UPDATE: I found an interesting post at Autism in New Brunswick about a University of Kentucky professor’s (Dr. Boyd Haley) skepticism of this research based on the idea that mercury exposure continued after thimerosal was supposedly removed from vaccines in California (see the press story here). The difficulty with Dr. Haley's argument is that I can't find any reliable data showing that the levels of mercury in vaccines continued to be higher than trace amounts after Thimerosal was taken out of vaccines. At least I can’t find any published studies in scientific journals of such effect. It is difficult to believe that after Thimerosal was removed there was not a reduction in mercury exposure. Arguing that mercury exposure remained stable implies that either Thimerosal was not actually removed, that the new non-Thimerosal vaccines were so delayed to reach Drs offices as to not affect the overall mercury exposure, or that somehow these children continued to be exposed to mercury through a difference source. Otherwise, the most rational conclusion is to assume that mercury exposure was significantly reduced after Thimerosal was pulled from the market and therefore a parallel reduction in new cases with autism is expected. Sadly this didn't happen.