The science community has pushed back at the latest claims that acetaminophen (aka paracetamol) is a key factor in the increased prevalence of autism spectrum disorder (ASD) in children, cautioning that existing research remains inconclusive and often excludes genetics, comorbidities and a suite of other factors, including increased awareness of neurodevelopmental conditions.
ASD and the genetically overlapping attention-deficit/hyperactivity disorder (ADHD) have been the focus of considerable research in recent years, looking at links between these neurodevelopmental conditions and everything from gestational diabetes to environmental factors such as prenatal exposure to prescription painkillers, plastics and heavy metals. Much like those investigations, the latest review does not present a single “cause” for a child developing ASD or ADHD. It also plays down the largest influence: genetics.
“This study does not present new experimental findings; rather, it synthesizes and critiques the existing evidence,” said Alex Polyakov, a Clinical Associate Professor at the Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne. “Most of the studies considered in the review are retrospective in design – meaning they examine events after they have occurred. Such studies can highlight associations but cannot prove cause and effect. For example, one common reason pregnant women take paracetamol is to reduce fever. If later analyses show their children have higher rates of developmental difficulties, it is difficult to determine whether the medication itself was responsible or whether the fever contributed to the outcome.
“Retrospective research is also prone to biases – such as recall bias, publication bias and selection bias – that may distort results,” Polyakov added. “Statistical methods can reduce these issues, but they cannot fully eliminate them.”
Polyakov touches on a couple of the key issues with this new focus on acetaminophen: retrospective, observational correlation studies are fraught with confounders. For example, research could emerge that suggests wound coverings are linked to increased risk of infection, but inferring the wound covering is the issue negates other factors such as individual immune responses, dressing use, as well as lifestyle variables and other health comorbidities that influence infections, for example.
What we do know is that ASD and ADHD are both highly heritable, meaning that while scientists believe there are lifestyle factors that influence the conditions, the general consensus is that there is no one “cause.” In 2021, a large team of researchers found that, in a genome-wide-association-study (GWAS), ASD incidence appeared linked to an inherited variation in the DNA sequence at a single nucleotide – single nucleotide polymorphism (SNP) – in as many as 50% of cases. In addition to this, other genetic variants – again, highly heritable – are thought to drive around 80% of ASD cases.
“Autism spectrum disorder is a neurodevelopmental condition with significant clinical heterogeneity,” the researchers tabled. “Heritability estimates are high (~ 80%), and the genetic architecture is complex, involving de novo, rare and common genetic variants. One approach to disentangle this heterogeneity and understand how genetics contribute to autism-associated clinical features is through cohort datasets that combine deep phenotypic information with biological datasets.
“In autism, the majority of the genetic variation tracked by heritability is accounted for by common genetic variation, as quantified by the single nucleotide polymorphism (SNP)-based heritability which is estimated to be ~ 40–50%,” they continued.
So, given what we know – which is by no means a complete picture, except that ASD and ADHD are fundamentally part of our DNA – there are related health implications that could see pregnant women, with the genetic blueprint of neurodevelopmental conditions, more likely to use over-the-counter pain medication. Studies into the link between pain sensitivity and ASD/ADHD have emerged in recent years, suggesting that signaling dysregulation alters acute and chronic pain experiences for people with brains that biologically function differently.
“Research shows that both autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are predominantly driven by genetic factors, which account for around 70–80% of overall risk, while environmental influences together contribute only about 20–30%,” Polyakov said. “Among these environmental factors, many influences are involved – such as parental age, prematurity, maternal health conditions, and air pollution – each contributing only modestly. Any effect of paracetamol use in pregnancy is therefore likely to be very small relative to these much larger genetic influences. This means that even if paracetamol was completely eliminated during pregnancy, it would almost certainly have only a negligible impact on the overall prevalence of ADHD and ASD at the population level.”
In addition to all these factors, there’s the issue of scientific study design. Scientists have a responsibility to do all they can to remove data biases, but how the data is collected, what statistical modeling is applied and how results are inferred play a huge role in study outcomes. This side of research can get lost in the discussion surrounding those studies. And this is one point scientists highlight in the wake of the latest review.
“A recent review in the US has reported associations between prenatal paracetamol use and slightly higher rates of autism, but a large Swedish study using sibling comparisons had found no effect when family factors were controlled,” said Kevin Yap, an Adjunct Associate Professor in the School of Psychology and Public Health at La Trobe University and a Clinical Associate Professor in the Surgery Academic Clinical Programme at Duke-NUS Medical School. “The observational studies in the US review differ in design (e.g. self-report vs prescription data), exposure timing and duration, and how other confounders were adjusted – therefore, the results of this study have to be taken with caution.”
Ultimately, any new announcements about ASD and acetaminophen/paracetamol should be viewed with caution, keeping in mind what scientists have already found: Results of studies are mixed, ASD and ADHD is highly complex and not well understood, and pointing at a single “cause” sets a dangerous precedent in cherrypicking research.
“Autism is a neurodevelopmental condition with no known single cause,” said Dr Hannah Kirk, a Research Fellow at Monash University. “However, research shows that genetics play a large role, with hundreds of genes being linked to autism. Recent suggestions that Tylenol use during pregnancy could increase the risk of autism has understandably raised concern among expectant parents. However, no study has shown that acetaminophen, the main ingredient in Tylenol, causes autism. Some studies have reported an association between acetaminophen use and autism, while others have not. Importantly, association does not mean causation.
“A recent large-scale study, which analyzed data from 2.48 million births, found that when researchers compared siblings (a method to control for genetic and environmental factors) any apparent links between acetaminophen and autism disappeared,” she added. “This suggests that other factors such as genetic or underlying maternal health conditions may better explain the findings.
“It’s also worth noting that fever itself has been linked to adverse pregnancy outcomes. In many cases treating a fever with acetaminophen may reduce those risks. Pregnant people should continue to follow the advice of their healthcare providers when managing pain and fever.”
The rise in ASD and ADHD diagnoses has been in the spotlight in recent years, which involves many factors: changes in diagnostic measures, better access to services, increased understanding of the spectrum of neurodevelopmental conditions and how they present in women, who have historically been misdiagnosed from childhood, and adults becoming aware of their own diagnosis after navigating the autism journey with a child.
Medical advice has always been to consult with healthcare providers during pregnancy before taking any medication.
“The balance of evidence indicates that prolonged or high-dose use of paracetamol during pregnancy may carry risks for the child, whereas occasional or short-term use is unlikely to be harmful,” said Polyakov. “This conclusion aligns with a broader principle in medicine: all medications should be used cautiously, only when clearly necessary, at the lowest effective dose, and for the shortest possible time. This guidance is particularly important in pregnancy, when many alternatives to paracetamol for pain and fever management have well-established risks that are considerably greater.”
Professor Andrew Whitehouse, the Angela Wright Bennett Professor of Autism Research at The Kids Research Institute Australia, added: “Autism is a complex condition influenced by many genetic and environmental factors. Any small associations in this area need to be weighed against the risk of untreated high fever in pregnancy for the woman and the developing baby.”
Meanwhile, the US Food and Drug Administration (FDA) has announced it would advance the approval of leucovorin (brand name Wellcovorin), a decades-old folinic acid medication for cerebral folate deficiency (CFD), which has also been linked to ASD. Leucovorin is a form of folate, an essential B vitamin, or B9. It has previously been approved by FDA for counteracting the toxic effects of certain cancer drugs, like methotrexate, which block the body’s use of folate. To date, just four small, randomized trials that all used different doses and benchmarks of success have investigated leucovorin’s usefulness in reducing ASD risk during pregnancy or to treat symptoms in children. The single study cited in this move by the FDA is a 2024 trial of just 40 individuals. Overall, the science is inconclusive and more work in this area is needed.
Finally, it’s also worth remembering that, ultimately, ASD and ADHD are neurodevelopmental conditions – unlike research into disease, there is no “cure,” and treating them as something to “fix” continues to perpetuate the idea that people with neurodiversity have something wrong with them, not something different. Living on the ASD and/or ADHD spectrum also presents a spectrum of challenges, but advocates suggest the “fix” should be more focused on society than the individual, so these differences can be better supported and ultimately benefit everyone.
“We know that autism is not just a disability,” said Professor Simon Baron-Cohen, Director of the UK’s Autism Research Centre. “It’s also a difference, and sometimes those differences include strengths or even talents. And I think that side of autism has got neglected.”
For more on those strengths, we recommend revisiting some fascinating studies looking into human evolution and how long neurodiversity has existed in and helped the survival of human populations.
Source: Scimex
