Tylenol, Autism, and Apples to Apples

While the White House Monday stressed a possible connection between Tylenol use among pregnant woman and autism, the body of research paints a far more complex reality.

By Martin Davis
EDITOR-IN-CHIEF
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Photo by Peter Burdon on Unsplash

Editor’s Note: The following piece covers statements made by the White House on Monday regarding Tylenol use and a link to autism, and research carried out by scientists exploring that connection. This piece does not offer medical advice, and people should always defer to their physician on matters of care and medication.

On Monday the White House released a statement saying that “Evidence Suggests Link Between Acetaminophen, Autism.” That announcement drew rebuke from a number of quarters, including the Society for Maternal-Fetal Medicine, which released a statement saying, in part:

To be clear, SMFM stands behind our recommendation that acetaminophen use during pregnancy has not been shown to cause or increase the risk of autism or other neurobehavioral problems in children.

On Monday evening, the Advance joined a call sponsored by SciLine featuring Dr. Brian Lee of Drexel University. Lee is co-author of a study published last year in JAMA, “Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability,” which followed 2,480,797 children born between 1995 and 2019 in Sweden, with follow-up through December 31, 2021.

That study concluded that “Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analysis.”

Understanding the discrepancy in these positions requires better understanding the research being cited.

Apples to Oranges

Lee said that the study published in JAMA by himself and his coauthors is a “two-part story.”

When Lee and his coauthors looked at the kids of mothers who used acetaminophen, the active ingredient in Tylenol, during pregnancy and those who didn’t use acetaminophen, “we found a slight statistical increase in risk of autism and ADHD.”

But does this mean that acetaminophen is causing autism and ADHD?

“When we look at users [of acetaminophen] versus non-users,” Lee said, “this is kind of an apples to oranges comparison because the users are so different in many ways.”

He notes, for example, that people taking acetaminophen are sicker than those who aren’t taking the medicine because “they have a medical condition that needs treatment.”

The other issue concerns the connection between neurodevelopmental disorders and genetics.

“Autism is a highly heritable condition,” Lees said, “and … when you just look at users versus non-users, it sort of ignores that aspect.”

Apples to Apples

To ensure their study accounted for genetics and, thus, was comparing apples to apples, Lee and his coauthors “looked at siblings born to the same mother,” he said, where “one sibling was exposed and the other sibling was unexposed.”

Under these conditions, Lee said, “the apparent risk completely flatlined and disappeared. In other words, there was no increase in risk of autism or ADHD associated with acetaminophen use. And what that told us was that familial confounding factors such as maternal genetics were likely explaining the apparent statistical association.”

What about Leucovorin?

Prior to the White House’s statements about acetaminophen, the Food and Drug Administration published a notice to the Federal Register approving a form of Leucovorin as a possible treatment for autism, according to a piece published by Reuters.

Lee was asked about this and responded that it’s “premature.”

The drug, according to the Mayo Clinic, “acts the same way in the body as folic acid” and is currently used to offset the “harmful effects of methotrexate (a cancer medicine).”

Lee stated that folic acid “affects neurodevelopment.” The challenge with “promoting Leucovorin at this time is that the existing evidence” for the drug alleviating symptoms associated with autism “is remarkably premature. There's only been a handful of very small studies which have some methodological issues. … In short, more research is needed.”

Stand-alone Study?

Research exploring links between acetaminophen and autism are still fairly new. According to Lee, the studies tend to fall into two large camps.

Studies that engage in “sibling control analysis,” as Lee’s and others’ have done, are showing an emerging “consensus … that for the studies that are actually controlling for genetics and familial confounding, those studies are not supporting that a causal association exists between acetaminophen use and autism.”

On the other hand, Lee said, “the sort of apples to oranges studies just looking at folks who use [acetaminophen] versus folks who don't use,” Lee said, “they’re finding the small increase in risk.”

Talk with Your Physician

As with any treatment, patients need to talk with their physician about the best treatment course for them.

Lee noted, for example, that “fevers are a known quantity as far as potential adverse effects” on a developing fetus. “Certainly the evidence base for fevers being harmful,” he continued, “is a lot stronger in my opinion, than for acetaminophen being harmful. At least at recommended doses.”

However, he also stressed that he is not a clinician and that “this is one of those areas where you should talk to your doctor.”

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