Questions about the cause and treatment of autism and other neurodevelopmental disorders (NDDs) have been in the news lately, and the Canadian Paediatric Society has received a number of queries from members looking for guidance. With the input of subject-matter experts, we have prepared this document to help you answer questions from patients and families.

The CPS promotes responsible communication of evidence-based guidance and encourages paediatricians to combat misinformation in a way that supports patients and families. It is crucial to avoid describing NDDs as a consequence of any single risk factor. This framing can cause unnecessary worry and guilt for parents. The CPS also advocates for the voices, perspectives, and experiences of people with autism and their families to be amplified in these conversations.

Acetaminophen use during pregnancy

Fever in pregnancy, especially in the first and second trimesters, is associated with a higher risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder, and the risk seems to be increased for recurrent or prolonged fever. The CPS—along with the Society of Obstetricians and Gynaecologists of Canada and Health Canada—advises pregnant people to manage fever effectively, and if acetaminophen is needed, to use an appropriate dose for the shortest duration necessary to control symptoms. Pregnant people should avoid excessive use of acetaminophen, and always check with their healthcare provider if they are unsure about dose or timing.

Parents and families may have heard that some observational studies have shown an association between acetaminophen use in pregnancy and NDDs. This association is referred to as “confounding by indication” and can be explained this way: We know that fever itself increases ASD risk, and pregnant people take acetaminophen to treat fever. So is the association with NDDs due to acetaminophen or with the fever itself? Statistical adjustments cannot perfectly tease this out.

Two studies in particular have received most of the media attention:

• A study published in August 2025, and the subject of most of the attention, explored the acetaminophen-NDD connection using a novel method designed to synthesize diverse streams of evidence. Several factors put this study at high risk of bias, including: potential intellectual conflict of interest, lack of information about how the studies were adjudicated; the authors adjudicating the studies not blinded to the results; and the systematic review not pre-registered on any database.
• A large Swedish study showed increased ASD with self-reported acetaminophen use, but when researchers compared siblings, they found that the link disappeared. This suggests that the association between acetaminophen and ASD is probably due to unmeasured genetic or environmental factors. But because the study was not a randomized trial, other biases cannot be completely ruled out. The study also didn’t capture details like the dose, how long acetaminophen was taken, or exactly when it was used during pregnancy.

Based on the available evidence, CPS advice continues to be to manage fever in pregnancy effectively, according to health provider advice and product dosing recommendations.

Use of leucovorin in patients with autism

Leucovorin, the trade name for folinic acid, is a water-soluble folate analog used to decrease the toxic effects of methotrexate. In high doses, it is used for cancer treatment and for certain types of anemia. It has also been used in individuals with documented reduced cerebral folate levels. Some parents are asking health professionals to initiate Leucovorin for their children with autism.

Although some studies have reported higher levels of anti-folate receptor antibodies in some people with autism, it’s not known whether those antibodies actually reduce brain levels of folate or whether reduced folate levels is the cause of their autism. Some people have suggested—with anecdotal evidence—that Leucovorin would likely be effective in treating autistic patients with these autoantibodies.

To date, there have been 5 clinical trials of Leucovorin in people with autism: Two examined how response varied by antibody status. In one study, patients with the antibody showed slightly more benefit for the main outcome that was examined: language skills. However, despite the mild benefit, language skills remained significantly delayed and parents themselves did not report improvement in communication skills. In the second study, there was no clear association between changes in Leucovorin response and antibody status, as assessed using a parent report measure of autistic features. The other trials reportedly showing a response to Leucovorin involved small numbers of participants and/or other limitations that make it difficult to be confident of the results. There was no indication in these trials of examples of dramatic improvement.

In summary, there is insufficient evidence for the use of Leucovorin in the treatment of autism currently. While the use of Leucovorin may set up unrealistic expectations in parents looking for a “magic bullet,” it is unlikely to provide any benefit based on existing evidence.

Sincere thanks to the following members for the development and review of this information:

Dr. Souvik Mitra, Chair, CPS Fetus and Newborn Committee

Dr. Scott McLeod, Chair, CPS Mental Health and Developmental Disabilities Committee

Dr. Lonnie Zwaigenbaum

Dr. Sam Wong, CPS Director of Medical Affairs

Posted: October 7, 2025