Does paracetamol use in pregnancy cause autism? Experts respond

Australia’s Chief Medical Officer and Therapeutics Goods Administration (TGA) have joined with medicines regulators, clinicians and scientists worldwide in rejecting claims made by US President Donald Trump regarding the use in pregnancy of paracetamol (known as acetaminophen or Tylenol in the United States) and the subsequent risk of babies developing attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD).

White House Press Secretary Karoline Leavitt said there is “mounting evidence finding a connection between acetaminophen use during pregnancy and autism”, with the White House website referencing multiple studies which have found an association between the two. The most recent of these, led by the Icahn School of Medicine at Mount Sinai and published in the journal BMC Environmental Health in August this year, analysed 46 studies incorporating data from more than 100,000 participants across multiple countries using the Navigation Guide Systematic Review methodology.

According to Mount Sinai’s Assistant Professor Diddier Prada, “Our findings show that higher-quality studies are more likely to show a link between prenatal acetaminophen exposure and increased risks of autism and ADHD.” The paper also explored biological mechanisms that could explain the association between acetaminophen use and these disorders, noting that acetaminophen is known to cross the placental barrier and may trigger oxidative stress, disrupt hormones, and cause epigenetic changes that interfere with fetal brain development.

The researchers went on to call for cautious, time-limited use of acetaminophen during pregnancy under medical supervision; updated clinical guidelines to better balance the benefits and risks; and further research to confirm their findings and identify safer alternatives for managing pain and fever in expectant mothers. They also acknowledged that their study does not show that acetaminophen directly causes neurodevelopmental disorders, with Prada noting that untreated pain or fever in pregnancy can be harmful to fetuses and that pregnant women should not stop taking medication without consulting a doctor.

But this call for caution hasn’t stopped Trump and US Health and Human Services (HHS) Secretary Robert F Kennedy Jr from instructing the Food and Drug Administration (FDA) to initiate a label change for acetaminophen to reflect that its use by pregnant women may be associated with an increased risk of autism and ADHD in children, and to issue a letter encouraging clinicians to prescribe the lowest effective dose for the shortest duration when treatment is required. The FDA acknowledges that a causal relationship has not been established; that other studies show no association at all; that acetaminophen remains the safest over-the-counter option in pregnancy among all analgesics and antipyretics; and that there can be risks for untreated fever in pregnancy, both for the mother and the fetus. 

The FDA has also published a Federal Register notice outlining a label update for leucovorin — a form of folic acid — for cerebral folate deficiency, which has been associated with autism. The change will authorise leucovorin treatment for children with ASD, with continued use if children show language, social or adaptive gains. The HHS recognises that leucovorin is not a cure for ASD and may only lead to improvements in speech-related deficits for a subset of children with ASD; furthermore, it must be administered under close medical supervision and in conjunction with other non-pharmacological approaches for children with ASD, such as behavioural therapy.

Here in Australia, the TGA has stressed that paracetamol is considered safe for use in pregnancy when used according to directions in TGA-approved Product Information (PI) and Consumer Medicines Information (CMI) documents; this means that a medicine has been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other harmful effects on the fetus having been observed. International peer regulators, including the Medicine and Healthcare products Regulatory Agency (MHRA) in the UK, have reiterated that paracetamol should continue to be used in line with product information documents.

The TGA said its advice on medicines in pregnancy is based on rigorous assessment of the best available scientific evidence, and that any new evidence that could affect its recommendations is carefully evaluated by its independent scientific experts. The TGA is aware of published articles suggesting an association between maternal paracetamol use and childhood autism, but said these have methodological limitations and that more robust studies have refuted these claims.

Various expert commentators have also weighed in on the news. Gino Pecoraro OAM, Associate Professor of Obstetrics and Gynaecology at The University of Queensland and President of the National Association of Specialist Obstetricians and Gynaecologists (NASOG), admitted that numerous studies have found association between paracetamol use and ASD but said none have found causation.

“Even in the studies suggesting association the effect is very mild, with only a 0.1% increased rate (from 1.33% to 1.42%) in the largest Swedish study looking at 2.5 million children born between 1995 and 2019,” Pecoraro said. “These changes were more likely explained by confounding issues rather than drugs having been taken. Furthermore, twin studies of fraternal twins whose mothers had taken paracetamol during pregnancy did not find concordance, with very few cases that both twins were affected.”

Dr Ian Musgrave, a Senior Lecturer in the Faculty of Medicine at The University of Adelaide, acknowledged that there has been some alarm in the general public about the increasing incidence of autism in the population, but said this is due to increased awareness among parents and clinicians and broadening diagnostic substitution.

“After decades of research we know that autism is a multigenomic developmental disorder, with 80% hereditability,” Musgrave said. “Environmental factors are involved as well, such as parental age and fever during pregnancy.” This last factor suggests that it could be riskier to avoid paracetamol during pregnancy than to take it, as noted by Alex Polyakov — a Clinical Associate Professor at The University of Melbourne and Medical Director of Genea Fertility Melbourne.

“One common reason pregnant women take paracetamol is to reduce fever,” Polyakov stated. “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.”

While Polyakov agrees that prolonged or high-dose use of paracetamol during pregnancy may carry risks for the child, he ultimately believes that any risk of triggering autism is likely to be very small relative to 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,” he said.

As for the FDA’s authorisation of leucovorin as a treatment for ASD, the experts remain sceptical.

“Leucovorin (folinic acid) has been promoted as a ‘treatment’ for autism, but the evidence is weak,” said Professor Andrew Whitehouse from The Kids Research Institute Australia. “A few small trials suggest possible small improvements in behavioural outcomes, yet these studies are limited by small numbers, inconsistent findings and a lack of independent replication.

“Right now, the science does not come close to the standard needed to recommend leucovorin in the clinical management of autism. The field lacks large, multisite, rigorously controlled trials that could confirm whether benefits are real, reproducible and meaningful in everyday life.”

Professor Adam Guastella, from Children’s Hospital Westmead Clinical School and The University of Sydney, said that “the evidence about the use of leucovorin as a treatment for autism, either provided in pregnancy or to children with autism, is preliminary and requires stronger scientific studies to ensure safety and effectiveness. There are some promising studies suggesting possible benefits, but these studies have many limitations that suggest that further research is needed.”

Guastella added that “there are also some studies suggesting negative side effects. More work is needed to be certain about the correct dose and timing, particularly when given in pregnancy and early childhood, before being taken up as a treatment for the community.”

Finally, Professor Dawn Adams from La Trobe University said the suggestion of using leucovorin to ‘treat’ autism is worrying because such statements impact how people understand and perceive autism.

“Autism is not something that needs treating or to be cured; it’s a neurodevelopmental difference,” Adams said. “When we frame it as a condition that needs ‘fixing’, we risk adding to the stigma autistic people already face.

“What really makes a difference for autistic people is the right supports: inclusive classrooms, workplaces that adapt to needs, communities that understand communication and sensory differences, and policies shaped by good-quality research.

“Autistic people don’t need treatments or cures. They need a world that accepts and values them for who they are.”

Image credit: iStock.com/damircudic