ADHD Risk Higher With Prenatal Acetaminophen Exposure

Prenatal acetaminophen exposure is associated with increased odds of attention-deficit/hyperactivity disorder (ADHD), according to a prospective study.

"Evidence is certainly mounting against the safety of acetaminophen exposure during gestation," Brennan H. Baker of Columbia University Mailman School of Public Health, in New York City, told Reuters Health by email. "However, I still think it is too early to translate these findings into a clinical recommendation."

Previous studies have raised concerns that acetaminophen might impair fetal brain development, and recent meta-analyses of observational studies support an association between prenatal acetaminophen exposure and ADHD, autism spectrum disorder, and hyperkinetic disorder/hyperactivity symptoms. These studies, however, used maternal self-report of acetaminophen exposure.

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Baker and colleagues used data from the Gestation and the Environment cohort in Sherbrooke, Canada, to evaluate the association between acetaminophen levels measured directly in meconium (which reflect cumulative exposure during the last two-thirds of pregnancy) and the development of ADHD by age 6 to 7 years.

Among the 345 children included in the study, acetaminophen was detected in the meconium of 199 (57.7%), and ADHD was diagnosed in 33 (9.6%).

Acetaminophen detection in meconium was associated with 2.43-fold increased odds of ADHD at age 6 to 7 years (95% confidence interval, 1.41 to 4.21), the researchers report in JAMA Pediatrics.

Low levels of acetaminophen exposure did not significantly modify the odds of ADHD, compared with no acetaminophen exposure, but the highest tertile of acetaminophen exposure was associated with 4.10-fold increased odds of ADHD (95% CI, 2.41 to 6.95).

Each doubling of meconium acetaminophen level was associated with a 10% increase in the odds of ADHD (95% CI, 1.02 to 1.19).

In functional connectivity analyses, children with detectable levels of acetaminophen in meconium demonstrated increased negative connectivity between the medial prefrontal cortex gyrus and six clusters covering regions of bilateral precentral and postcentral gyri, superior parietal lobules, and supramarginal gyri, as well as increased negative connectivity between the left lateral prefrontal cortex and a cluster spanning portions of the right precentral and frontal gyrus.

Children with decreased connectivity were more hyperactive, and causal mediation analysis suggested an indirect effect of meconium acetaminophen on increased hyperactivity mediated through frontoparietal network and right precentral/frontal gyrus connectivity.

"I am currently working on randomized mouse experiments testing this association," Baker said. "If the association holds in an experimental setting, that will indicate that the association between prenatal acetaminophen and offspring ADHD is likely causal. Then we could use this mouse model to investigate the underlying mechanisms and develop an intervention."

In the meantime, he said, "there may be no other good pharmaceutical options for pain and fever relief in pregnant women. Other antipyretics like aspirin and ibuprofen also have associated risks when used during pregnancy, such as pregnancy loss, miscarriage, or birth defects. (And) prior studies have shown that untreated fevers may be associated with adverse neurodevelopmental outcomes, including autism. So, there must be some way to handle fevers during pregnancy, because the consequences of not treating a fever could be just as bad or worse than taking acetaminophen. More thorough research could potentially tease out this fine line."

—Will Boggs, MD

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