A new population-based study led by Drexel University Dornsife School of Public Health in Philadelphia calls that into question. Models without sibling controls pointed to marginally increased risks of autism and attention-deficit/hyperactivity disorder (ADHD) associated with acetaminophen use during pregnancy, the researchers reported. They emphasized, however, that analyses of matched full-sibling pairs found no evidence of increased risk of autism (hazard ratio [HR], 0.98), ADHD (HR, 0.98), or intellectual disability (HR, 1.01) associated with acetaminophen use.
“Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analyses,” the study team wrote in an article in the Journal of the American Medical Association. “This suggests that associations observed in other models may have been attributable to confounding.”
The authors noted that several studies suggest acetaminophen (or paracetamol) use during pregnancy could increase risk of neurodevelopmental disorders in children, adding, “If true, this would have substantial implications for management of pain and fever during pregnancy.”
Their nationwide cohort study with sibling control analysis study sought to examine the associations of acetaminophen use during pregnancy with children’s risk of autism, ADHD, and intellectual disability. It included a population-based sample of about 2.5 million children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021.
Antenatal and prescription records were used to document use of acetaminophen during pregnancy, while autism, ADHD, and intellectual disability diagnoses were based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers.
The results indicated that 185,909 children (7.49%) were exposed to acetaminophen during pregnancy. “Crude absolute risks at 10 years of age for those not exposed vs. those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability,” the researchers pointed out.
They added that in models without sibling control, ever-use versus no-use of acetaminophen during pregnancy was associated with marginally increased risk of autism (HR, 1.05; 95% CI, 1.02-1.08); risk difference [RD] at age 10 years, 0.09%; 95% CI, –0.01% to 0.20%); ADHD (HR, 1.07; 95% CI, 1.05-1.10; RD, 0.21%; 95% CI, 0.08%-0.34%); and intellectual disability (HR, 1.05; 95% CI, 1.00-1.10; RD, 0.04%; 95% CI, –0.04% to 0.12%).
To address unobserved confounding, the study team also analyzed matched full-sibling pairs. “Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, –0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, –0.02% [95% CI, –0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, –0.10% to 0.13%]),” the researchers wrote. “Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively.”
The study concluded that acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analysis and that confounding might have influenced the results of another model that suggested otherwise.
The FDA considers acetaminophen to pose minimal risk during pregnancy, and, as a result, the drug is commonly used to manage pain and fever during pregnancy. A 2021 consensus statement by an international group of scientists and clinicians recommended, however, that pregnant individuals “forego [acetaminophen] unless its use is medically indicated,” among other precautionary actions, due to potential risk of developmental disorders such as autism and attention-deficit/hyperactivity disorder (ADHD).”
“Multiple biases may explain the associations observed in previous studies between acetaminophen use and neurodevelopmental disorders,” the authors of the current study suggested. “Confounding by indication may occur based on the reasons that acetaminophen was taken, e.g., due to infection, fever, migraine, or pain from autoimmune disease. These indications for acetaminophen use may be risk factors for neurodevelopmental disorders and may thus result in spurious associations.”
The researchers added that confounding by parental health and genetics is likely because neurodevelopmental disorders are highly heritable. Acetaminophen users during pregnancy have reported a higher prevalence of multiple health conditions associated with neurodevelopmental disorders compared with nonusers.
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