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Taking acetaminophen (Tylenol) during pregnancy was not associated with the development of autism or attention deficit-hyperactivity disorder (ADHD) in children, a large Swedish nationwide cohort study found.

Models without sibling control showed slightly higher risks of neurodevelopmental diagnoses at age 10 in kids exposed to acetaminophen (HR 1.05, 95% CI 1.02-1.08 for autism; HR 1.07, 95% CI 1.05-1.10 for ADHD; and HR 1.05, 95% CI 1.00-1.10 for intellectual disability), according to Brian Lee, PhD, of the Drexel University Dornsife School of Public Health in Philadelphia, and colleagues.

However, sibling control analyses of ever-use versus no use of acetaminophen revealed no associations (HR 0.98, 95% CI 0.93-1.04 for autism; HR 0.98, 95% CI 0.94-1.02 for ADHD; and HR 1.01, 95% CI 0.92-1.10 for intellectual disability), Lee and colleagues reported .

Nor was there any dose-response pattern in the sibling control analyses with neurodevelopmental diagnoses for low, medium, and high daily acetaminophen use compared with no acetaminophen use. For example, HRs for autism were 0.85, 0.96, and 0.88, respectively.

"We think that all of our analyses together indicate that there is substantial evidence that the correlation between use of acetaminophen during pregnancy and children's risk of neurodevelopmental disorders is not likely due to a causal relationship between the two," co-author Renee Gardner, PhD, of the Karolinska Institute in Stockholm, told MedPage Today.

In recent years, there has been a slew of lawsuits claiming that taking acetaminophen in pregnancy caused autism or ADHD in children. However, in December, the judge handling the consolidated mass tort litigation from testifying since they did not adequately support these claims with evidence.

Still, some smaller studies had found ties between acetaminophen use in pregnancy and autism or ADHD, and in 2021, a consensus statement cautioning against using acetaminophen in pregnancy was published in Nature Reviews Endocrinology, though many physicians thought the statement sent the wrong message to patients.

Gardner said that "there was a strong response to that statement, including a number of letters published in the same journal disputing the conclusions and pointing out that such 'calls for action' run the risk of adding to anxiety and guilt among pregnant women."

Authors of the current study concluded that their sibling control analyses suggest that "associations observed in models without sibling control may have been attributable to confounding." They also noted that "there was not one single 'smoking gun' confounder," but the parents' health and sociodemographic characteristics may have played a role.

Lee said he hoped the research was "generally reassuring to expectant parents who might experience anxiety when suffering from pain or fever during pregnancy" and that it would provide more information for physicians to address patient concerns about the risk for neurodevelopmental conditions in their children.

Pamela Berens, MD, an ob/gyn at the McGovern Medical School at UTHealth Houston who wasn't involved in the study, told MedPage Today she doesn't want her patients "unnecessarily suffering" because of older research linking acetaminophen to autism, which had made some of her patients wary. Berens said the study's large cohort size was noteworthy and it provides reassurance "that these drugs themselves are likely not what is causing the finding and the other studies -- it's likely something that's confounding those studies."

Researchers analyzed nearly 2.5 million singleton children born in Sweden from 1995 to 2019 and followed up through 2021 (median follow up 13.4 years); 185,909 were exposed to acetaminophen in pregnancy. Children were excluded if there was missing information about the birthing parent's age, residence, education, or income. Acetaminophen exposure was prospectively collected by physicians and midwives starting at the first prenatal visit, supplemented by the Medical Birth Register and a register of drug prescriptions.

In total, 7.62% children were diagnosed with at least one neurodevelopmental condition: 2.76% with autism, 5.9% with ADHD, and 0.99% with intellectual disability.

Without sibling control, crude absolute risks at age 10 for neurodevelopmental diagnoses were slightly higher for those exposed to acetaminophen compared to those not exposed (1.53% vs 1.33% for autism; 2.87% vs 2.46% for ADHD; and 0.82% vs. 0.70% for intellectual disability). In sibling control analyses, however, absolute risk differences were negligible, they reported.

The researchers noted that acetaminophen had similar risks for neurodevelopmental disorders as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and anti-migraine medicines. In sibling analyses, aspirin was actually inversely associated with neurodevelopmental disorders, a finding that Lee said the team plans to investigate, though they hypothesize this is because aspirin is used for women at risk for preeclampsia.

The paper had several limitations, including the fact that diagnoses were not validated, that tracing exposure through prenatal data plus prescription dispensing may miss some dosing data, and that people likely used acetaminophen for reasons that don't require inpatient or outpatient medical care, like headaches, which would not have been captured.

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