Saturday, September 10, 2011

Induced Autism

I ran across a recently published paper the other day that had a long title that didn't make much at first glance - "Prenatal exposure to ß2-adrenergic receptor agonists and risk of autism spectrum disorders".  According to the abstract1, this paper looked at exposure to ß2 adrenergic receptor agonists during the prenatal period and found that, in general, they did not increase the risk of having a child with autism.

So at first I though it was simply yet another paper ruling out a relationship between a type of drug and autism.  But then there was this little line that caught my attention -
However, terbutaline exposure for > 2 days during the third trimester was associated with more than a fourfold increased risk for ASDs independent of indication although the limited sample size resulted in an imprecise and nonsignificant effect estimate (OR(adj) = 4.4; 95% confidence interval, 0.8-24.6).
I didn't know what terbutaline was (or for that matter what a ß2 adrenergic receptor agonists was) but a four fold increase of autism is nothing to sneeze at.  So I exercised my google Phd and went and found out that, in general, ß2 adrenergic receptor agonists are a class of drugs that are used to treat asthma and other lung problems and that terbutaline is just the name of a specific drug of this type.

But it turns out that terbutaline is/was also used, off-label, to delay preterm labor.  So here you have a drug that has been used to delay preterm labor that might greatly increase the risk of autism.  That definitely isn't good.

On the flip side, this result is based on a small number of cases so can't just assume that the relationship is going to be the same in the general population.  But then again, this isn't the first study to suggest that neonatal exposure to terbutaline might increase the risk of autism.

Other studies have found that fraternal twins who were exposed to terbutaline for longer than two weeks had an increased chance of both having autism2, that rats who were exposed to a large dose of terbutaline showed signs of neuroinflammation3, and that certain forms of genes related to the beta2-adrenergic receptor might be more common in people with autism4.

So while there is some room for doubt, I think it is safe to say that the risk is real.  Prolonged prenatal exposure to terbutaline probably does increase the risk of autism.  The good news is (if any of this can be good) that the FDA issued a warning earlier this year about prolonged use of terbutaline for treating preterm labor -
The U.S. Food and Drug Administration is warning that terbutaline administered by injection or through an infusion pump should not be used in pregnant women for prevention or prolonged (beyond 48-72 hours) treatment of preterm labor due to the potential for serious maternal heart problems and death. In addition, oral terbutaline tablets should not be used for prevention or treatment of preterm labor. The FDA is requiring the addition of a Boxed Warning and Contraindication to the drug prescribing information (labeling) to warn against these uses.
Hopefully the medical community will get the message.


1. Croen LA, Connors SL, Matevia M, Qian Y, Newschaffer C, Zimmerman AW. Prenatal exposure to ß2-adrenergic receptor agonists and risk of autism spectrum disorders. J Neurodev Disord. 2011 Aug 27. [Epub ahead of print]
PubMed PMID: 21874331 DOI: 10.1007/s11689-011-9093-4 (Open Access)

2. Connors SL, Crowell DE, Eberhart CG, Copeland J, Newschaffer CJ, Spence SJ, Zimmerman AW. beta2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins. J Child Neurol. 2005 Nov;20(11):876-84.
PubMed PMID: 16417856

3. Zerrate MC, Pletnikov M, Connors SL, Vargas DL, Seidler FJ, Zimmerman AW, Slotkin TA, Pardo CA. Neuroinflammation and behavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism. J Pharmacol Exp  Ther. 2007 Jul;322(1):16-22. Epub 2007 Mar 30.
PubMed PMID: 17400887 DOI: jpet.107.121483 (Open Access)

4. Cheslack-Postava K, Fallin MD, Avramopoulos D, Connors SL, Zimmerman AW, Eberhart CG, Newschaffer CJ. beta2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort. Mol Psychiatry. 2007 Mar;12(3):283-91. Epub 2007 Jan 2.
PubMed PMID: 17199132 DOI:


  1. Hi MJ -

    Neat paper that I haven't gotten a chance to read in full yet. This finding, especially alongside the animal model of terbetuline exposure, makes for difficult times for the people hell bent on a mission to deny a pathological component to the immune dysregulation found in autism.

    When the first neuroinflammation paper came out (Vargas 2005), there was a lot of hemming and hawing about the possibility that the ongoing immune response wasn't necessarily pathological, and in fact, it might be benificial. In some instances (i.e., some authors of the Vargas paper, I think this was likely an attempt to keep desperate parents from trying all kinds of crazy things on their children.

    We've learned a lot about the immune involvement in the brain since that time, and the idea that an ongoing state of inflammation might not be a problem, much less potentially benificial, is increasingly difficult to defend.

    In the case of the animal model of terbetuline exposure and resultant, chronic microglial activation and behavioral abnormalities, there really wasn't anything else that might be causing problems, there wasn't any conceivable benificial effect that could be postulated.

    With the benifit of a couple of years of research and hindsight, it seems likely that the mechanism of action in animal models is one of immune programming.

    While the increased risk of women getting a two day blast of terbutaline is significant, likely real, and needs more investigation, I think the bigger picture message is more meaningful; another line of evidence that immune dysfunction in autism is likely pathological in cases where it is present. That is seriously inconvenient.

    - pD

  2. Sad title. I hope we come to the truth soon.

    ADHD used to be termed Minimal Brain Damage.

  3. Hi pD,

    I never really understood why people go set uncomfortable about the idea that biology can impact behaviors. If there is a major biological disruption, i.e. chronic neuroinflammation, it makes complete sense that there is going to be some physical or behavioral sign of it.

    Instead people like to talk about autism being "genetic" or a "difference" without seeming to realize that the difference is going to cause changes or disruptions to the underlying biology.

  4. Brain Behav Immun. 2011 Aug 28. The role of immune dysfunction in the pathophysiology of autism.
    Onore C, Careaga M, Ashwood P.
    SourceDepartment of Medical Microbiology and Immunology, University of California, Davis, CA, USA; The Medical Investigation of Neurodevelopmental Disorders (M.I.N.D) Institute, UC Davis Health System, Sacramento, CA, USA.

    Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD.