No Solid Evidence Linking Paracetamol to Autism

On September 22, the U.S. Food and Drug Administration (FDA) announced that there is evidence suggesting that use of the common painkiller paracetamol during pregnancy “may be associated with an increased risk” of neurological conditions such as autism and attention deficit hyperactivity disorder (ADHD) in children. The FDA indicated its intention to include this possible association on the drug’s labeling. 

At a press briefing attended by President Trump and U.S. Secretary of Health Robert Kennedy Jr., both reiterated the statement and further referred to vaccines as a potential contributor to autism. This subject has been extensively studied in recent years, and studies have  consistently found no causal link between vaccination and autism.

The FDA’s announcement regarding paracetamol was based primarily on a review study published last month, which pointed to a possible link between the drug and various neurodevelopmental disorders. The review assessed 46 studies, including eight that specifically addressed autism.  Twenty-seven of the studies reported a small increase in the risk of neurological problems in children exposed to paracetamol in utero. However, the authors or the review emphasized that the findings were not conclusive, and they did not recommend avoidance of paracetamol during pregnancy.

Many physicians and researchers have criticized the FDA’s announcement, arguing that the scientific evidence is insufficient to infer causality between paracetamol exposure and autism—or any other condition. They caution that premature warnings of this kind are more likely to produce harm than benefit.

“The better-controlled studies are less likely to find even a small risk [from taking paracetamol],” noted Helen Tager-Flusberg, a psychologist who studies autism at Boston University in Massachusetts, in an interview with the scientific journal Nature. “And even then, what we’re talking about is a minor association. We do not think that taking acetaminophen is in any way contributing to actually causing autism.”

Ann Bauer, an epidemiologist and co-author of the review study, similarly expressed concern that the agency’s statement was premature. “I think those of us in the research community would like to see stronger evidence,” she said in an interview with NPR.

“At the heart of this is people trying to look for simple answers to complex problems,” commented James Cusack, Chief Executive of the UK research charity Autistica, who is himself autistic, in an interview with Nature.

What Evidence Links Prenatal Paracetamol Exposure to Autism?

Some studies have reported a very slight increase in autism diagnoses among children whose mothers took paracetamol during pregnancy. However, studies with stronger methodological controls, designed to rule out the influence of other factors, generally do not show such an increase.

For example, one of the largest studies ever conducted on the subject – a cohort study of 2.5 million children in Sweden published last year – found that 1.53 percent of children exposed to paracetamol in utero were diagnosed with autism, compared with 1.33 percent of children whose mothers did not take the drug during pregnancy.

This represents a small but statistically significant increase. If these were the only data available, one might infer that a small proportion of autism cases could be linked to paracetamol use. However, the same study also conducted sibling comparisons, examining pairs in which one child had been exposed to paracetamol in utero while the other had not.  Siblings share approximately half of their genome, as well as both the intrauterine environment and the postnatal family environment.  Therefore, if differences in autism risk were observed between siblings, it would provide stronger evidence that paracetamol was the causal factor—since this would be one of the few variables distinguishing them.  In this analysis, however, no differences were found between exposed and unexposed siblings.

For this reason, the researchers concluded that their findings do not support an association between paracetamol use during pregnancy and autism.

Why Do Some Studies Report a Link?

How can we explain the findings—both in this study and in others—that have reported some association between paracetamol use during pregnancy and autism?

The most likely explanation lies in the influence of confounding factors. Studying the effects of paracetamol use is particularly challenging. Because it is an over-the-counter drug, there are no precise medical records documenting its use. As a result, most studies rely on self-reports by mothers or on midwife questionnaires, both of which may be subject to recall bias or inaccuracy.

In addition, paracetamol is widely used as an analgesic and antipyretic. Women experiencing medical conditions that cause pain or fever are, by necessity, more likely to take it than healthy women. As a result, an observed correlation between paracetamol use and autism may not reflect a causal effect of the drug itself, but instead indicate an association between autism and the underlying maternal condition, or with episodes of high maternal fever during pregnancy.

Indeed, a large cohort study conducted in Japan, which involved more than 200,000 children, reported a slight increase in autism diagnoses among those whose mothers used paracetamol during pregnancy. However, the researchers emphasized that this increase could be accounted for by the involvement of confounding factors.

If There Might Be a Link, Why Take the Risk?

If there is uncertainty about the safety of paracetamol, should expectant mothers be advised to avoid the drug during pregnancy? Many physicians argue not, warning that such recommendations could cause more harm than benefit.

First, issuing a public statement about a connection—one that has not been scientifically established—between paracetamol and autism could  induce guilt among mothers of autistic children and heighten anxiety in pregnant women. “We risk placing blame on mothers and causing more stress, self-blame and stigma, despite having no evidence to support such claims,” said Viktor Ahlqvist, an epidemiologist at the Karolinska Institute in Stockholm and co-author of the Swedish study.

In addition, paracetamol cannot be compared to foods such as raw fish, which can be avoided without significant consequence. Women will still need effective relief from pain and fever during pregnancy, and there are virtually no safe alternatives to paracetamol. “Pain relief for pregnant women is woefully lacking,” said Monique Botha, a social and developmental psychologist at Durham University, UK. “Paracetamol is a much safer pain-relief option during pregnancy than basically any other alternative.”

Avoiding medication altogether is also neither a safe nor practical option. Such avoidance would inevitably result in considerable suffering for pregnant women. Moreover, studies have demonstrated an association between high maternal fever during pregnancy and miscarriages, as well as various fetal complications, including neurodevelopmental conditions such as autism.

“The evidence does not support a causal link between acetaminophen or vaccines and autism,” concluded Sura Alwan, a researcher at the University of British Columbia in Vancouver, Canada, who specializes in congenital anomalies. “Suggesting otherwise may fuel misinformation and undermine confidence in safe treatments and immunizations.”