Paracetamol During Pregnancy Could Be Linked to Increased Risk of ADHD and Autism

A new international study shows that Acetaminophen (paracetamol) use during pregnancy may be linked to an increased risk of childhood attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

What is Acetaminophen?

Acetaminophen, or paracetamol, is the most commonly used drug to prevent or reduce fever and to relieve pain amongst mothers during pregnancy and infants in early life. Despite its use in this context, previous studies in both animal models and humans suggest a link between prenatal paracetamol exposure and increased risk of conditions such as; asthma, cryptorchidism, and ADHD and ASD. Human studies have shown that paracetamol can cross the placental barrier and can remain in an infant’s circulation for a long duration.

In adults (with normal liver function) approximately 5–10% of paracetamol is processed into a highly toxic metabolite called N-acetyl-p-benzoquinoneimine – which is responsible for the hepatotoxicity (chemical-driven liver damage) of paracetamol and is detoxified as 3-(N-acetyl-L-cystein-S-yl)-acetaminophen. Due to a neonate’s limited capacity to metabolize the toxic metabolites, they can remain for a longer duration, resulting in increased in utero exposure.

Jeffrey Keelan, Deputy Director of the Women and Infants Research Foundation, University of Western Australia commented on the available evidence linking paracetamol exposure in pregnancy and neurodevelopmental conditions: “There is considerable evidence from a variety of studies that suggests there is a link between paracetamol (Acetaminophen) exposure in pregnancy and an increased risk of neurodevelopmental/behavioral problems, such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD).”

“However, due to the nature of the evidence and potential uncertainties in its interpretation, there is still considerable debate as to whether or not there is sufficient evidence to formally advise women against taking this medication during pregnancy.”

Study aim and design

The study, published in JAMA Psychiatry, aimed to examine the prospective link between cord plasma paracetamol metabolites and the following physician-diagnosed conditions; ADHD, ASD, ADHD and ASD, and developmental disabilities in childhood. Nine hundred and ninety-six mother-infant dyads were analyzed; they were enrolled at birth and followed up prospectively from 1998 to 2018.

There were 996 participants studied (55% male) with a mean age of 9.8 years. The 996 participants had the following diagnoses:

• 25.8% – ADHD only
• 6.6% – ASD only
• 4.2% – ADHD and ASD
• 30.5% – other developmental disabilities
• 32.8% – Neurotypical (individuals of typical developmental, intellectual, and cognitive abilities)

Umbilical cord blood samples were examined for traces of paracetamol. Paracetamol metabolites were measured using umbilical cord plasma samples that had been collected at birth – maternal plasma paracetamol metabolites were also collected within three days of delivery. Levels of metabolite in both samples were measured using liquid chromatography–tandem mass spectrometry.

The study concluded that “cord biomarkers of fetal exposure to paracetamol were linked to a significantly increased risk of childhood ADHD and ASD in a dose-response fashion.”

Anthony J. Hannan, NHMRC Principal Research Fellow from The Florey Institute of Neuroscience and Mental Health, University of Melbourne and Melbourne Brain Centre, provided expert comment on the study findings:

"This new research article provides additional evidence that a woman’s use of the common drug paracetamol during pregnancy could increase the risk of two major disorders of brain development, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Both disorders result from complex combinations of genetic and environmental factors which remain poorly understood.”

He adds: “This new evidence raises important public health issues. Can pregnant women avoid taking this drug without compromising their own health? Much more research into the causes of ASD and ADHD is required. Furthermore, if women are advised to not take paracetamol during pregnancy, then alternative treatments to this drug need to be explored, which will also require more research."

Strengths and limitations of the study

The study authors explain that whilst their findings support previous findings that show there is indeed a link between perinatal paracetamol exposure and childhood neurodevelopmental risk – additional investigation is warranted.

Keelan explains that the Ji, et al. study has added to the debate as to whether or not there is enough evidence to advise women against taking paracetamol whilst pregnant – however there are still questions that remain to be answered.

“The strengths of the study are that, for the first time, we have actual blood paracetamol measurements to link exposure and dose with outcome, rather than indirect evidence of exposure at some point in pregnancy. The study also is quite large, adding to its power.”

There are in Keelan’s opinion, also some significant weaknesses.

“Firstly, there is no information on the indications for maternal paracetamol use in the hours before delivery, so we don’t know whether or not it is the reason for taking paracetamol that is the important causal link. Secondly, there is no other information on prior paracetamol taking during pregnancy, so we don’t know whether or not the infants with high levels in their systems also had repeated exposures earlier on in pregnancy because of a pattern of regular maternal paracetamol use. Thirdly, most previous studies have focused on mid-pregnancy exposure as a likely time for potential disruption of important neurodevelopmental processes in utero, not the peripartum period.”

“Finally, and most significantly, every sample in the cohort had detectable levels of paracetamol, raising the possibility that either a) the paracetamol assay lacked specificity and there was some sort of interference present, or b) all mothers in the cohort had taken paracetamol prior to or during labor and delivery, raising concerns around the nature of the cohort and the ability to compare exposure with no exposure."

Reference

Ji, et al. (2019) Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood. JAMA Psychiatry. DOI: 10.1001/jamapsychiatry.2019.3259

Expert comment on the above findings were given by Anthony J. Hannan and Jeffrey Keelan. These comments were sourced via the Australian Science Media Centre.