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Acetaminophen (Tylenol) in pregnancy was tied to increased risk of attention deficit-hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in a prospective cohort study, researchers said.

Among 996 mother-child pairs, those with higher levels of acetaminophen exposure -- measured through biomarkers in cord blood at delivery -- the chances that offspring would be diagnosed later with ADHD or ASD were significantly greater, reported Xiaobin Wang, MD, MPH, of Johns Hopkins University Bloomberg School of Public Health in Baltimore, Maryland, and colleagues in .

Wang and colleagues calculated an odds ratio of 2.86 for ADHD diagnosis for infants in the highest tertile of acetaminophen exposure versus the lowest (95% CI 1.77-4.67).

Similarly, the odds ratio for ASD diagnosis was 3.62 for the highest versus lowest tertiles (95% CI 1.62-8.60).

"For a long time, acetaminophen [was] considered [one of] the few safe pain and fever relief medications during pregnancy," Wang told MedPage Today in an email. "However, previous studies based on maternal self-report and our study based on acetaminophen metabolite biomarkers showed consistent findings between prenatal acetaminophen exposure and increased risk of ADHD risk, and possibly, ASD as well."

Noteworthy Limitations

It's not the first study to link fetal exposure to acetaminophen to subsequent behavioral problems for children, nor the first .

However, rather than suggesting pregnant women avoid acetaminophen altogether, these findings imply providers and patients should together weigh the risks and benefits of using the over-the-counter medication during pregnancy, particularly since other options for pain relief, like nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with adverse outcomes for babies, said Kimford J. Meador, MD, of Stanford University in Palo Alto, California, who was not involved in this research.

Importantly, the data presented by Wang and her team were not adjusted for family history of ADHD and ASD, nor for genetic factors related to risk for these conditions, Meador said.

It was also not adjusted for other medications that may have been used during childbirth, such as anticonvulsant drugs or anesthetic agents, Meador added. Another important point was that acetaminophen exposure was measured only once in study participants -- at delivery -- meaning the full extent and timing of acetaminophen exposure could not be evaluated.

"[The authors] didn't look at exposure in pregnancy and particularly the third trimester, which is a particularly susceptible time," Meador told MedPage Today, adding that animal studies have demonstrated that the fetal brain is most vulnerable during the third trimester to alcohol and anticonvulsant drugs, for example.

Another limitation was that acetaminophen sulfate was not measured, meaning the composite acetaminophen burden on newborns was incomplete.

Study Details, Further Findings

The study involved participants in the who had sufficient cord plasma samples for metabolite assays. Acetaminophen exposure was measured through two metabolites -- glucuronide and 3-(N-acetyl-L-cysteine-S-yl)-acetaminophen -- as well as a composite measure of both, in cord blood collected at birth.

Children were evaluated at a mean age of about 10; 25.8% were diagnosed with ADHD, 6.6% with ASD, and 4.2% with both. Just over 30% were diagnosed with other developmental disorders and the remaining one-third were neurotypical.

Mothers and children differed significantly between groups. Mothers of children with ADHD or ASD, for example, were more likely to have higher body mass indexes, feel stressed during pregnancy, or report smoking or drinking before or during pregnancy compared to mothers who had neurotypical children. On the other hand, children with ADHD and ASD were more likely to be male, born preterm, and have lower birth weights than their neurotypical counterparts.

Notably, all mothers tested positive for unchanged acetaminophen in samples collected at birth, meaning there was no non-exposed group for reference, the authors wrote.

Children in the highest tertile of cord unchanged acetaminophen were more likely to be diagnosed with both ADHD and ASD compared to those in the lowest tertile (OR 3.38, 95% CI 1.25-9.85), but no relationship was found between the other metabolites and the dual diagnosis.

Associations between acetaminophen exposure and neurodevelopmental outcomes were attenuated but remained significant after adjusting for child sex; maternal race/ethnicity; preterm birth; breastfeeding; maternal tobacco, alcohol or illicit drug use; child lead levels; stress during pregnancy; maternal fever; and child age at last visit.

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