Countless news cycles have been spent discussing potential causes of autism and other neurodevelopmental disorders, many (most?) of which have historically involved unfairly and unscientifically blaming mothers. Several rounds in more recent years have been dedicated to acetaminophen, a popular fever and pain medication commonly known by the name brand Tylenol in the United States. This has left many parents confused and anxious over the decision to take what is generally considered to be a safe* medication for fever or aches and pains during pregnancy when other options, such as NSAIDS, have potential for causing serious problems.
To be fair, there have been several studies showing a potential link between use of this medication during pregnancy and adverse neurodevelopmental outcomes in children. In 2021, Nature Reviews Endocrinology published a Consensus Statement supported by 91 “scientists, clinicians and public health professionals from across the globe” that called the safety of acetaminophen into question:
We recommend that APAP should be used by pregnant women cautiously at the lowest effective dose for the shortest possible time. Long-term or high-dose use should be limited to indications as advised by a health professional. Packaging should include warning labels including these recommendations. Given the high prevalence of APAP use by pregnant women, the public health implications of use reduction might be substantial.
https://www.nature.com/articles/%20s41574-021-00553-7
This is a bit more of an aggressive stance than what has been taken by the FDA or the American College of Obstetrics and Gynecology (ACOG). But it isn’t as if ACOG has been telling pregnant women to cram handfuls of acetaminophen down their gullets indiscriminately. In fact, here is their response to the Consensus Statement:
ACOG and obstetrician-gynecologists across the country have always identified acetaminophen as one of the only safe pain relievers for pregnant individuals during pregnancy. This consensus statement, and studies that have been conducted in the past, show no clear evidence that proves a direct relationship between the prudent use of acetaminophen during any trimester and fetal developmental issues.
Neurodevelopmental disorders, in particular, are multifactorial and very difficult to associate with a singular cause. The brain does not stop developing until at least 15 months of age, which leaves room for children to be exposed to a number of factors that could potentially lead to these issues.
The authors are not recommending anything counter to what is already done by obstetrician-gynecologists when prescribing acetaminophen for a given clinical condition. ACOG’s clinical guidance remains the same and physicians should not change clinical practice until definitive prospective research is done. Most importantly, patients should not be frightened away from the many benefits of acetaminophen. However, as always, any medication taken during pregnancy should be used only as needed, in moderation, and after the pregnant patient has consulted with their doctor.
https://www.acog.org/news/news-articles/2021/09/response-to-consensus-statement-on-paracetamol-use-during-pregnancy
In 2022, the inevitable lawsuits began piling up. These efforts targeted Johnson & Johnson, the manufacturer of Tylenol, but also companies that sell generic formulations like CVS, Walgreens, and Walmart. By October of that year, more than 500 of these lawsuits had been clumped together into one large federal multi-district litigation (MDL). In December of 2023, the judge presiding over the Tylenol MDL issued a ruling that appeared to signal an imminent dismissal:
Cote, in a 148-page ruling, found that none of the five expert witnesses proposed by the plaintiffs had offered a sound scientific methodology to support their opinion that Tylenol’s active ingredient, acetaminophen, could cause autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).
“Instead, the unstructured approach adopted by the plaintiffs’ experts permitted cherry-picking, allowed a results-driven analysis, and obscured the complexities, inconsistencies, and weaknesses in the underlying data,” she wrote.
https://www.reuters.com/legal/lawsuits-claiming-tylenol-causes-autism-lack-scientific-support-judge-finds-2023-12-19/
Just last month, however, Judge Cote allowed testimony of a new expert introduced by plaintiffs and the defense has until July to object. And there are also hundreds of potential state lawsuits waiting in the wings, so things might still get ugly. But a new study out of Sweden has provided the best evidence to date on this issue, and the Johnson & Johnson legal team is likely feeling much better about their chances right now.
The study, which was run by researchers at the Karolinska Institute and Drexel University and published in JAMA earlier this week, looked at associations of acetaminophen use during pregnancy with the risk of autism, ADHD, and intellectual disability in children. Researchers looked at the medical records of about 2.5 million Swedish children born between 1995 and 2019, which also included prenatal data. And, quite importantly, this is a cohort study with matched sibling control analysis that is more capable of accounting for potentially confounding variables than any previous investigation.
Again, the sibling controls are the key to why this study is more reliable. They looked at exposures and outcomes in sibling pairs with the same biological parents, meaning that they had similar genetics and environments, and this included many instances where a mother used acetaminophen with one pregnancy but not during the other. This additional layer of analysis revealed that there was no evidence of higher risk.
One interesting finding illustrates the potential for finding associations that can be misleading. In the study, parents with neurodevelopmental disorders were more likely to have used acetaminophen during pregnancy. Parents with autism, for example, are more likely to have children with autism because it is highly heritable:
It is estimated at least 50% of genetic risk is predicted by common genetic variation and another 15-20% is due to spontaneous mutations or predictable inheritance patterns. The remaining genetic risk is yet to be determined.
https://www.uclahealth.org/news/new-genetic-clues-uncovered-largest-study-families-with
The arrow of causality is much more likely to travel through the DNA shared with a developing fetus than through exposure to a medication. Acetaminophen use during pregnancy was also more prevalent with mothers in a lower socioeconomic class or who had psychiatric or neurodevelopmental conditions. We say that correlation does not equal causation a lot, mostly because it is true, and it looks like earlier studies were likely fooled by hidden confounding factors.
*Acetaminophen when taken in excessive amounts, usually but not always in the setting of an intentional overdose, can be extremely toxic and result in permanent liver failure and even death. Appropriate dosing, however, is extremely safe and has fewer potential side effects of concern than other pain and fever reducers such as ibuprofen and aspirin, especially in children. It is, in fact, the only safe OTC medication for these purposes in young infants.
