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

In this cohort study, the use of acetaminophen/paracetamol during pregnancy was not associated with a higher risk of autism, ADHD, or intellectual disability in children when non-exposed siblings were included as a control group.

Whether using acetaminophen (Tylenol, paracetamol) is associated with the risk of being diagnosed with autism spectrum disorder (ASD), ADHD, or intellectual disability (ID).

2,480,797 children (51% boys, 49% girls) in Sweden, 7.5% of whom were known to have been exposed to acetaminophen during pregnancy.

In this cohort study acetaminophen use was analyzed in 2 ways. The primary metric of interest was whether a mother ever used acetaminophen during pregnancy, compared to not at all. The secondary metric of interest was the quantity of acetaminophen used per day on average during pregnancy (a low, medium, or high dosage).

Acetaminophen use was further analyzed through 2 groups of participants: (i) all participants and (ii) in sibling-matched cases (i.e., children diagnosed with ASD, ADHD, or ID) and control groups (i.e., the sibling of a child diagnosed with ASD, ADHD, or ID, with the same biological parents).

The researchers adjusted their analyses for the following potential maternal confounders: 10 health conditions (including migraine and chronic pain), 6 classes of medication (e.g., nonsteroidal anti-inflammatory drugs other than acetaminophen, antimigraine medications), calendar period of delivery, parity (how many times the mother had given birth), age, religion, cohabitation at delivery, early pregnancy BMI, smoking, healthcare use, education, and income. The researchers also adjusted for infant birth cohort, sex, and country of birth.

After a median follow-up duration of 13 years, children born to mothers who reported ever using acetaminophen during pregnancy had a 5% higher risk of ASD, a 7% higher risk of ADHD, and a 5% higher risk of ID. However, none of these findings were statistically significant after the inclusion of sibling control comparisons.

Acetaminophen use during pregnancy and neurodevelopment outcomes

Similarly, after sibling control analyses, there was no association between low, medium, or higher dosages of acetaminophen (<166 mg/day, 166–429 mg/day, or >429 mg/day) and the risk of ASD, ADHD, or ID.

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.

In the summarized study, the researchers only captured data on acetaminophen use when the participants sought medical attention or filled prescriptions for acetaminophen. This would likely not include over-the-counter acetaminophen use for concerns such as mild headaches, back pain, muscle aches, or fevers.

Participants who took more acetaminophen tended to smoke more, be of lower socioeconomic status, have a higher early pregnancy BMI, and were more likely to be diagnosed with psychiatric conditions.