29 August 2012

Prenatal Risk Factors For Autism?

A New York Times opinion piece from last week by a research who argues for prenatal effects in the womb as a cause of some share of autism cases in a trade non-fiction book. Some of the key observations and evidentiary points from the scientific literature that the author is advocating for regarding the pressing health issue are as follows:

At least a subset of autism — perhaps one-third, and very likely more — looks like a type of inflammatory disease. And it begins in the womb. . . . In autistic individuals . . . [i]nflammatory signals dominate. Anti-inflammatory ones are inadequate. A state of chronic activation prevails. And the more skewed toward inflammation, the more acute the autistic symptoms.

Nowhere are the consequences of this dysregulation more evident than in the autistic brain. Spidery cells that help maintain neurons — called astroglia and microglia — are enlarged from chronic activation. Pro-inflammatory signaling molecules abound. Genes involved in inflammation are switched on. . . .

A population-wide study from Denmark spanning two decades of births indicates that infection during pregnancy increases the risk of autism in the child. Hospitalization for a viral infection, like the flu, during the first trimester of pregnancy triples the odds. Bacterial infection, including of the urinary tract, during the second trimester increases chances by 40 percent.

The . . . mother’s attempt to repel invaders — her inflammatory response — seems at fault. . . .Inflaming pregnant mice artificially — without a living infective agent — prompts behavioral problems in the young. In this model, autism results from collateral damage. It’s an unintended consequence of self-defense during pregnancy.

Yet to blame infections for the autism epidemic is folly. . . . the epidemiology doesn’t jibe. . . . Better clues to the causes of the autism phenomenon come from parallel “epidemics.” The prevalence of inflammatory diseases in general has increased significantly in the past 60 years. As a group, they include asthma, now estimated to affect 1 in 10 children — at least double the prevalence of 1980 — and autoimmune disorders, which afflict 1 in 20. Both are linked to autism, especially in the mother. One large Danish study, which included nearly 700,000 births over a decade, found that a mother’s rheumatoid arthritis, a degenerative disease of the joints, elevated a child’s risk of autism by 80 percent. Her celiac disease, an inflammatory disease prompted by proteins in wheat and other grains, increased it 350 percent. Genetic studies tell a similar tale. Gene variants associated with autoimmune disease — genes of the immune system — also increase the risk of autism, especially when they occur in the mother. . . .

Mothers of autistic children often have unique antibodies that bind to fetal brain proteins. A few years back, scientists . . . injected these antibodies into pregnant macaques. (Control animals got antibodies from mothers of typical children.) Animals whose mothers received “autistic” antibodies displayed repetitive behavior. They had trouble socializing with others in the troop. In this model, autism results from an attack on the developing fetus. . . .

A mother’s diagnosis of asthma or allergies during the second trimester of pregnancy increases her child’s risk of autism. . . . Amniotic fluid collected from Danish newborns who later developed autism looked mildly inflamed. . . .

Why are we so prone to inflammatory disorders? . . .

[P]eople living in environments that resemble our evolutionary past, full of microbes and parasites, don’t suffer from inflammatory diseases as frequently. . . . Generally speaking, autism also follows this pattern. It seems to be less prevalent in the developing world. Usually, epidemiologists fault lack of diagnosis for the apparent absence. A dearth of expertise in the disorder, the argument goes, gives a false impression of scarcity. Yet at least one Western doctor who specializes in autism has explicitly noted that, in a Cambodian population rife with parasites and acute infections, autism was nearly nonexistent.

For autoimmune and allergic diseases linked to autism, meanwhile, the evidence is compelling. . . . asthma and autism follow similar epidemiological patterns. They’re both more common in urban areas than rural; firstborns seem to be at greater risk; they disproportionately afflict young boys. In the context of allergic disease, the hygiene hypothesis — that we suffer from microbial deprivation — has long been invoked to explain these patterns. . . . it should apply to autism as well. (Why the male bias? Male fetuses, it turns out, are more sensitive to Mom’s inflammation than females.)

A few points of context and emphasis are in order here:

* A variety of past data has already established a very strong genetic component to autism associated with rare rather than common genetic variants (sometimes in the form of deletions and copy number variants, rather than specific SNPs), in a particular complex of genes with particular functions. A majority of all autism cases probably have a genetic basis, although the particular mutations that are involved in any particular case vary widely. Non-genetic pre-natal causes are, at most, an important cause of only a minority of autism case.

* The autoimmune hypothesis offered above is not exclusive of genetic causes. In a significant share of the up to one third of pre-natal inflamation associated cases cited, the inflamation has a genetic component. In those cases where there is not a genetic component, the mechanism described sounds like an epigenetic effect in many cases. Epigenetic effects can be hereditary, although unlike true genetic effects, they usually persist for only a few generations and can be induced during someone's lifetype by means other than mutations.

* Childhood vaccination does not cause autism. Few cases of non-causation are better established.

* Even in cases where the environmental effects described above are at work, autism is still congenital, i.e. present at birth. Indeed, all of the evidence of maternal inflamation during pregnancy increasing autism risk involved the first two-thirds of the pregnancy, with a significant share of that risk attributable to early parts of the pregnancy when the mother may not even know that she is pregnant. Autism has not been convincingly linked in published scientific studies to the child's diet or parenting styles, for example.

* Controlling inflamation during pregnancy poses its own risk, and can't be limited to the period when people know that they are pregnant alone since the high risk period is front loaded. Many, if not all, anti-inflammatory drugs may present their own risks to a fetus during pregnancy. The author of the article quoted above argues for a comprehensive rethinking of our public health measures to address the problems associated with an overly hygenic environment, without definitively proposing a single solution. But, this calls for a balancing analysis. Lack of hygene causes deadly and unpleasant diseases. Excessive hygene can promote succeptibility ot excessive autoimmune responses. Even though Cambodia has lower rates of autoimmune disorders and autism, very few people would trade that benefit for the overall public health harms associated with its relative lack of hygene. Some level of excessive autoimmune disfunction may be a price worth paying for a reduced incidence of infectious disease agents.

* Autism is the fever of mental health conditions. It is a common symptom of a disorder with a non-specific cause. Indeed, this is more than just an analogy. Autism symptoms, like fevers, appear to be associated with inflamation.

* Regardless of the epidemiology of autism, if a large subset of autism cases involve an autoimmune inflamation mechanism, then early diagnosis and treatment designed to reach that mechanism, particularly during period key to brain development, such as anti-inflammatory drugs, in theory, might be effective. Treatments designed to selectively reverse epigenetic methylation of a child's genome related to autoimmune function also look like a promising avenue to investigate. But, please don't rely on me in turning to a totally unproven theory as a medical treatment without advice from a doctor. I'm a lawyer with a solid background in mathematics who stays abreast of the literature, not a doctor.

* Universal health care has collective public health benefits. One reason that really good population genetic and epidemiological studies often come from Scandinavia is that countries like Denmark have comprehensive national medical records in a well indexed form that is linked to other data about the patients that can be used for medical research. Strict American medical privacy and human subjects research laws make these kinds of studies almost impossible to conduct in the United States with the same level of rigor and statistical power. Nothing has more statistical power than a complete data set for an entire national population.

1 comment:

mooreb4 said...

Andrew, I found your blog this AM. I found in your posts clear thinking and succinct writing. Keep up the good work. I would like to know a little more about you. I suppose I will have to read some more. Brian in Tallahassee.