Field of Science

Terbutaline and autism...or not

[Can being really freaking cold during pregnancy cause autism in your child? Dunno. Via Wikimedia Commons, of all places.]

Dr. Jay (a.k.a., um, "Dr. Jay") Gordon tweeted something this morning that gave me pause. His tweet read that "terbutaline for pre-term labor doesn't work" with a link provided and continued with "and might increase autism," with another link provided. Curious about this alleged association between autism and terbutaline (a beta2-adrenergic receptor agonist, used to open air passages on-label and to stop pre-term labor off-label), I went to that latter link provided. I was just oh-so-shattered only to find "autism" inserted out of the blue via a quote from one Richard Dodd, a senior partner with Cappolino Dodd Krebs LLP. A quick visit to Google U turned up the URL Yep. They turned to an attorney who specializes in malpractice suits for an extensive quote alleging a connection between autism and terbutaline. He and his firm are not alone in pushing the terbutaline-autism link.

I've got no dog in this hunt, as I never was exposed to terbutaline and neither were my children. I am also not in the pay of whoever it is who makes the stuff. But I'd never seen any final ruling substantiating this link, so I turned again to Google U, the post-grad version, Google Scholar. There, I happened to find this review-of-a-review by Rodier et al. in the American Journal of Obstetrics and Gynecology, entitled "Does treatment of premature labor with terbutaline increase the risk of autism spectrum disorders?" It's from the February 2011 issue. The answer, according to the authors who performed the review of another review by Witter et al., is as follows:

Beta-adrenergic agents have been used in pregnant women for the treatment of premature labor and for the treatment of asthma. Concerns have been expressed that exposure to terbutaline, which is a beta-2 adrenergic agonist, may increase the risk of autism spectrum disorders (ASDs) in the offspring. This hypothesis deserves critical review, given the number of patients who have been exposed to the drug in the last 2 decades. The results are important to both the obstetricians and patients who weigh the risks and benefits of interventions and to the pediatricians who counsel the families of affected children.

We conducted an examination of the human and animal studies that have been used to support this hypothesis in a recent review,1 and we have reached a different conclusion. We find no support for the hypothesis that the use of terbutaline as a tocolytic agent is associated with the subsequent development of ASDs.

They note that studies lack analysis of the role that prematurity itself may play in ASD and overlook the fact that premature labor itself may well be "evidence of injury."

The horrible piece that "Dr. Jay" linked to, in addition to turning to an injury lawyer for medical expertise, also contains the following completely unsubstantiated and somewhat oddly phrased statement:
Toxins and bad medical drugs, including vaccinations, are often the leading suspects of autism disorders.
That would be news to the people who are actually involved in autism research, say the ones who find evidence of a high level of genetic contribution to autism, those who engage in studies of copy number variation, and those who conducted studies of identical vs fraternal twins, finding concordance as high as 90%. But you'd better watch out for those "bad medical drugs."

It's beyond me why someone who is presumably trained in medicine would even have linked to an "article" like this. It goes off topic in describing the FDA's warning about the use of terbutaline in pre-term labor, which focuses on the potential harm to the pregnant woman and calls for doctors to stop this off-label use.

The "article" also refers to "recent" studies from a team at Duke University on the autism-terbutaline link. Those studies date to 2007 and 2005. I'm not saying that the Duke team is not onto something with the overall mechanism, but when their only reference to "these findings have been extended to include autism" is their own work, a study of dizygotic twins...that's not a case-closed argument, counselor.

The Duke research team further provides two citations to support the statement that " Indeed, a connection of organophosphate exposures to autism has been proposed." Unfortunately, the authors of one of the studies cited found a link in North America but not in Italy, and instead of concluding that perhaps there isn't a link, they determined that there was instead "regional specificity in gene-environment interactions." And it's not about terbutaline.

The second citation they provide, "Szpir M. New thinking on neurodevelopment. Environmental Health Perspectives 2006; 114:A101-A107," unfortunately devotes three paragraphs of serious consideration to the "thimerosal-autism" link--in 2005!--and mentions SafeMinds, of all things. In other words, it is a review/commentary, not a presentation of new data. These three citations are the only ones in the 2007 paper that the authors offer as support of a "terbutaline-autism" link. Only one is a study involving terbutaline, and it's their own work.

Of interest, this sort of sketchy citation history is one thing that the AJOG review-of-the-review focuses on. Indeed, Rodier et al. note the echo chamber effect. One of the human studies the Witter et al. review cited is really a case study with commentary by four pediatricians, none of whom offer support of a link between terbutaline exposure and the patient's symptoms. The citation simply doesn't support the assertion.

Of further interest, however, is that the next human study the Witter et al. review cites is...that same dizygotic twin study self-cited above, which happens to be the work of some of the authors on the Witter et al. review. In other words, they self-cited again. As Dory from Finding Nemo would say, "Echo! Echo! Echo!" Here's what Rodier et al. have to say about that study:

The second reference that is cited in the article is to a study that had been reported by several of the same authors of the review.13 The review states that the earlier paper demonstrated increased concordance for ASDs in dizygotic twins after terbutaline treatment in utero. However, a careful review of the data found no significant association of concordance with terbutaline exposure in the whole twin sample (36 cases). Only when the investigators divided the sample into smaller subgroups and focused on twin pairs who were both male and had no other cases of ASDs in their family were they able to find a significant association between drug exposure and outcome. This group of 16 twin pairs should have been at increased risk for ASDs because they were male and at decreased risk because of the absence of ASDs in their families. It is unclear why such a subgroup would ever be selected for study a priori. If it was selected a posteriori, then the results should be considered “hypothesis-generating” at best.

Rodier et al. effectively address the shortcomings of the three other human studies offered up--one doesn't draw a conclusion that's related to terbutaline use, another is a personal communication (unpublished information) that doesn't fit with what the abstract for the presentation says, and the third was, according to the authors, of a "peculiar" design involving eight autistic children from two families with completely uninformative results.

When Rodier et al. turn to the animal studies, they observe that
However, it is important to note that the studies that are cited come almost exclusively from 1 research group and use the same dose at the same stage of development for the same number of repeated doses. If there is any error in the dose or timing or duration of exposure that was chosen to mimic terbutaline as a tocolytic therapy, it is shared by all the articles that were cited.
Guess which "one research group" that is?

Somehow, this morning, thanks to "Dr. Jay," I've managed to uncover a self-echoing terbutaline-autism cottage industry involving lawyers and, separately, a Duke University research team. Unfortunately, it also happens to be the day that the review in AJOG came out directly addressing the data for the proposed link and finding it faulty. Sometimes, whether it's development or social media, it can be all about the timing.

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