Study links fetal acetaminophen exposure to increased risk of ADHD

Fetal acetaminophen exposure has been associated with an increased likelihood that a child will develop attention-deficit/hyperactivity disorder (ADHD), according to a study published Feb. 6 in Nature Mental Health.

Prior research shows that between 41% and 70% of pregnant women use acetaminophen during pregnancy to control pain or reduce fever. The drug, which is the active ingredient of many pain-relief medications, is one of the few considered safe to take during pregnancy by the U.S. Food and Drug Administration.

The new findings suggest, however, that doctors should carefully evaluate the potential risks and benefits of medications with acetaminophen for mothers during pregnancy, the researchers said.

Most of the prior studies asked women to self-report whether they had taken Tylenol or anything that contained acetaminophen.

Brennan Baker, lead author, researcher at Seattle Children's Research Institute

Baker also works in the lab of Dr. Sheela Sathyanarayana, a UW Medicine pediatrician.

"This medication was also approved decades ago, and may need reevaluation by the FDA," said Sathyanarayana, the paper's senior author. "Acetaminophen was never evaluated for fetal exposures in relation to long-term neurodevelopmental impacts."

Acetaminophen is widely used during pregnancy, with 41–70% of pregnant individuals in the United States, Europe and Asia reporting use. Despite acetaminophen's classification as low risk by regulatory agencies such as the FDA, accumulating evidence suggests a potential link between prenatal acetaminophen exposure and adverse neurodevelopmental outcomes, including ADHD and autism spectrum disorder, the researchers noted.

This research tracked a cohort of 307 African American women from 2006 to 2011, who agreed to give blood samples during their pregnancy. The researchers tracked plasma biomarkers for acetaminophen in the samples.

The children born to these mothers were followed for 8 to 10 years. Among the women who did not use acetaminophen during pregnancy, the rate of ADHD was 8.6%, but for the women who used acetaminophen, the ADHD rate among their offspring was 17.7%.

Acetaminophen metabolites were detected in 20.2% of maternal plasma samples. Children whose mothers had these biomarkers present in their plasma had a 3.15 times higher likelihood of an ADHD diagnosis (95% confidence interval 1.20–8.29) compared with those without detected exposure.

The association was stronger among daughters than sons, with the daughters of acetaminophen-exposed mothers showing a 6.16 times higher likelihood of ADHD (1.58–24.05 confidence interval), while the association was weaker and nonsignificant in males. Researchers did not know why the association was stronger in females.

The investigators' analysis used data from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) research cohort, which comprised 1,031 pregnant individuals in Memphis, Tenn., who were enrolled between 2006 and 2011.

By happenstance, and not by design, the study cohort included only Black women, Baker said, adding that while the results are relevant, further research is needed to determine whether these findings apply to broader populations.

Mothers often are advised to turn to acetaminophen, the primary agent in Tylenol, rather than ibuprofen, which is more likely to adversely affect the fetal kidney or heart, Baker said.

"(Acetaminophen) is really the only option to control fever or pain during pregnancy," he said.

So, what is a mother to do?

"There is obviously more work that needs to be done in this area," he said. "And we need to continually update our guidance."

For example, he suggested, during prenatal visits, patients should discuss the dosage of a drug that contains acetaminophen or talk about what pain it is intended to help manage, he said. Another drug class, such as triptans, is safe and effective for managing migraines, he added.

More work needs to be done to find out if some people can tolerate acetaminophen during pregnancy with no ill effects on the fetus while others cannot, he said.

He added that this study does not establish a causal relationship between acetaminophen exposure and ADHD, and that research findings on the effects of the drug and its potential risks during pregnancy have been inconsistent.

One study recently released in Sweden showed no link between maternal acetaminophen use and ADHD in their children, while another study out of Norway did in fact find a link. The Swedish study, however, relied on self-reported data, which may have underestimated exposure.

"The study out of Sweden, however, reported that only 7% of pregnant individuals used acetaminophen," Baker noted. "And that study could have underestimated the exposure."

"I think it goes back to how the data was collected," he added. "The conflicting results mean that more research is needed."

Medical societies and the FDA should update guidance on the use of acetaminophen as more rigorous safety data emerge, Sathyanarayana said.