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Prenatal exposure to acetaminophen was linked with a subsequent increased risk of behavioral problems in children, even after controlling for multiple confounders, a small cohort from a U.K. study found.

Maternal use of acetaminophen especially during the third trimester (32 weeks) was associated with a higher risk of conduct disorders, emotional problems, and problems with hyperactivity when children were 7 years old, reported , of University of Bristol in the U.K., and colleagues.

Notably, these associations remained, even after adjusting for a variety of confounders, including both maternal prenatal and postnatal acetaminophen use, as well as genetic factors -- such as an index of ADHD genetic risk in mothers. Overall, 5% of children had behavioral problems.

"[This] suggests that the association ... is not explained by unmeasured familial factors linked to both acetaminophen use and childhood behavioral problems and that the findings are consistent with an intrauterine effect," the researchers wrote. "Our results could have important implications for public health advice, which currently considers acetaminophen safe to use during pregnancy."

Writing in , the authors analyzed data from the U.K. prospective birth cohort, the (ALSPAC), which enrolled 7,796 pregnant women from 1991 to 1992. Among those women 53% used acetaminophen during the third semester and 42% used the drug in the second semester.

The authors found that the risk of emotional and hyperactivity problems was also associated with acetaminophen use in the second trimester (18 weeks), though the risk was slightly lower than use of the drug in the third trimester.

Overall, maternal prenatal acetaminophen use in the third trimester was linked with an increased risk of several maternal-reported behavior problems in children from the , including:

• 46% higher odds of "total difficulties" (RR 1.46, 95% CI 1.21-1.77)
• 42% higher odds of conduct problems (RR 1.42, 95% CI 1.25-1.62)
• 31% higher odds of hyperactivity symptoms (RR 1.31, 95% CI 1.16-1.49)
• 29% higher odds of emotional problems (RR 1.29, 95% CI 1.09-1.53)

Second trimester use was linked with 23% higher odds of hyperactivity symptoms and 20% higher odds of conduct problems.

The authors argued that the timing of the drug might be important, with also showing stronger associations between risk of behavioral problems and maternal acetaminophen use in the third trimester, as opposed to the second trimester.

"Given that there is active brain development and growth during the third trimester, this finding could indicate that there are developmental periods when the brain is more sensitive to acetaminophen exposure," they wrote.

There are several hypotheses for the mechanisms surrounding the effect acetaminophen use may have on fetal neurodevelopment, including the endocrine-disrupting properties of the drug or the disruption of brain development through oxidative stress.

"Further studies are required to elucidate mechanisms behind this association as well as to test alternatives to a causal explanation," the authors concluded.

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