Children may have a higher risk of developing ADHD if their mothers used paracetamol – also known as acetaminophen – during pregnancy, adding weight to the contested link between the painkiller and foetal brain development, according to a small study.
While far from conclusive, the finding lends weight to the contested idea that the widely used pain reliever may affect foetal brain development, reports New Scientist.
Previous studies on paracetamol and neurodevelopmental conditions have provided conflicting findings. For instance, a 2019 study involving more than 4 700 children and their mothers linked use of the painkiller in pregnancy with a 20% greater risk of children developing ADHD.
However, an analysis published last year of nearly 2.5m children showed no such association when comparing siblings who either were or were not exposed to paracetamol before birth.
One issue is that most of these studies rely on self-reported medication use, a significant limitation given that people may not remember taking paracetamol while pregnant. For example, only 7% of participants in the 2019 study reported using paracetamol during pregnancy, far below the 50% seen in other studies.
“A lot of people take (paracetamol) without knowing it,” said Brennan Baker at the University of Washington in Seattle. “It could be the active ingredient in some cold medication you’re using, and you don’t necessarily know.”
So, Baker and his colleagues used a more accurate metric instead. They looked for markers of the medicine in blood samples collected from 307 women, all of whom were black and lived in Tennessee, during their second trimester.
None of them was taking medications for chronic conditions or had known pregnancy complications. The researchers then followed up with participants once their children were between eight and 10-years-old. In the US, about 8% of children between five and 11-years-old have ADHD.
On average, children whose mothers had markers of paracetamol in their blood were three times as likely to be diagnosed with ADHD than children born to mothers who did not – even after adjusting for factors like the mother’s age, pre-pregnancy body mass index (BMI), socioeconomic status and mental health conditions among their immediate family.
This suggests that using paracetamol during pregnancy may raise children’s risk of developing ADHD.
It is, however, also possible that the actual factor raising ADHD risk is whatever led someone to take paracetamol in the first place, rather than the drug itself.
“They haven’t been able to account for things like the mother’s reason for taking paracetamol, such as headaches or fevers or pains or infections, which we know are risk factors for adverse child development,” said Viktor Ahlqvist at the Karolinska Institute in Sweden.
But Baker believes it is the drug itself that is responsible. A subsequent analysis of tissue samples from 174 of the participants’ placentas showed that those using paracetamol had distinct metabolic and immune system changes. These changes are similar to those seen in studies that tested the effects of paracetamol in pregnant animals without an infection or underlying health condition.
“The fact we see the immune upregulation in animal models as well, I think, really strengthens the case for causality,” said Baker.
“There is a lot of prior work showing that elevated immune activation during pregnancy is linked with adverse neurodevelopment.”
Still, these findings are far from conclusive. For one thing, the study included a small number of participants, all of whom were black and lived in the same city – limiting the generalisability of the findings.
For another, it only measured blood markers of paracetamol at one moment in time. These markers stick around for about three days, so the study probably captured more frequent users, and there may be a dose-dependent effect, said Baker.
“Paracetamol is currently the first-line therapeutic option for pain and fever in pregnancy,” he added. “But I think agencies like the US Food and Drug Administration and different obstetric and gynaecology associations need to be continually reviewing all available research and updating their guidance.”
Study details
Associations of maternal blood biomarkers of prenatal APAP exposure with placental gene expression and child attention deficit hyperactivity disorder
Brennan Baker, Theo Bammler, Emily Barrett et al.
Published in Nature Mental Health on 6 February 2025
Abstract
Despite evidence linking prenatal acetaminophen (APAP) exposure and adverse neurodevelopment in humans and animals, more than half of pregnant women in most populations use APAP. Prior studies could be biased by inaccurate self-reported APAP use, and the molecular mechanisms linking prenatal APAP with adverse neurodevelopment are unknown. Here we estimated associations between maternal plasma biomarkers of APAP exposure, child attention deficit hyperactivity disorder (ADHD) and placental gene expression in 307 African American mother–child pairs. Overall, detection of APAP in second trimester plasma was associated with higher odds for child ADHD diagnosis (odds ratio of 3.15 (95% confidence interval 1.20 to 8.29)). Prenatal APAP exposure and ADHD were associated with placental upregulation of immune system pathways in females and downregulation of oxidative phosphorylation in both sexes. In females only, prenatal APAP was associated with 5.22% higher odds (0.0456–13.1%) of ADHD statistically, mediated through increased immunoglobulin heavy constant gamma 1 (IGHG1) expression. These results highlight placental molecular mechanisms that may underlie developmental toxicity of prenatal APAP exposure.
See more from MedicalBrief archives:
Paracetamol: Precautions necessary during pregnancy — Consensus Statement
Painkillers during pregnancy could affect fertility of the unborn child