Like the summarized study, larger studies using nonsibling matched analyses have tended to show an association between acetaminophen use and neurodevelopmental condition risk even after controlling for many confounding factors.

A 2020 umbrella review of 35 meta-analyses concluded there was an association between acetaminophen and ADHD, with the evidence rated by the researchers as convincing.^[1] Furthermore, a 2023 meta-analysis found an association between acetaminophen and ADHD, though the researchers noted the evidence was of overall low quality.^[2] Unlike the 2023 meta-analysis, a 2019 meta-analysis concluded that the association between acetaminophen and ADHD may be due to confounding because controlling for additional factors in 5 of 7 studies reduced the effect sizes originally found in those studies. However, in the other 2 studies, effect sizes increased when more confounders were controlled for.^[3] Another 2019 meta-analysis noted a significant association between acetaminophen and ADHD and stronger associations in the third trimester, as well as when acetaminophen dosage was taken for more than 28 days. This study reported that 6 of 8 studies examined were high quality.^[4] In addition, there were 2 other meta-analyses in 2021 and 2018 that also noted associations between acetaminophen and ADHD and ASD.^[5]^[6]

Two recent cohort studies, not included in these meta-analyses, showed mixed results overall. In a 2024 cohort study that asked about acetaminophen use prospectively at 6 times in pregnancy, rather than asking mothers after birth to recall when they used acetaminophen during pregnancy, the researchers observed greater attention problems at age 4 with maternal acetaminophen use.^[7] Conversely, in a 2023 cohort study, there was no association found between acetaminophen use and overall cognitive development. In addition, there was no increased risk in late pregnancy compared to other time points during pregnancy, though the researchers only measured acetaminophen use up until week 32 (of 40 weeks, on average) of gestation.^[8]

There are mechanisms that could explain why acetaminophen could affect neurodevelopment. Acetaminophen crosses the placenta and reaches the fetus, where it can stimulate the endocannabinoid system, alter BDNF levels, inhibit Cox-2 (an inflammatory pathway), and affect inflammation-induced immune activation.^[1]^[4]^[9]

However, it’s unclear whether these mechanisms would be expected to result in neurological disorders. And the existing observational research is limited by the possibility of unaccounted for confounders, making causation elusive.

However, a very useful tool to reduce uncontrolled confounders in some areas of observational research is comparing sibling pairs. Fortunately, there are 2 other studies in this subject area, besides the summarized study, that have included sibling pairs.

A 2013 study found that, in sibling-control analysis, acetaminophen use was associated with poorer motor development outcomes, and use for more than 28 days was associated with poorer communication, externalizing behavior (which can include lower attention or increased aggression), and internalizing behavior (i.e., emotional health) outcomes. However, the researchers did not analyze rates of diagnosed ASD or ADHD.^[10]

In the other sibling pair study, researchers found that long-term exposure to acetaminophen (at least 29 days) was associated with a higher risk of ADHD diagnosis, but this association disappeared after including sibling controls.^[11]

In summary, the majority of meta-analyses have reported an association between acetaminophen use and a higher risk of neurodevelopmental disorders. However, these findings are based on observational research, in which causation is difficult to establish. Furthermore, when siblings were used as control groups in order to control for uncontrolled confounders, there were no such associations present.

Strictly speaking, based on the overall evidence, there may be increased risks to the neurodevelopmental health of the offspring from using acetaminophen during pregnancy, especially with long-term use (e.g., for over 28 days), and perhaps with use during the third trimester.^[2]^[4] Prospective parents should discuss their health situation with their healthcare providers so that they can make an informed decision about the pros and potential cons of acetaminophen use for their health, as well as the health of their offspring.

Is acetaminophen (Tylenol) use during pregnancy associated with an increased risk of neurodevelopmental conditions? Original paper