November 13, 2025
3 min read
Key takeaways:
- Clinicians should prioritize harm mitigation if prescribing leucovorin.
- The AAP requires results from at least one large, multicenter, randomized clinical trial to update its current guidance.
The American Academy of Pediatrics declined to recommend routine use of leucovorin for children with autism spectrum disorder, according to interim guidance released by the organization.
In a press release, the AAP said that children with ASD deserve access to evidence-based care supported by high-quality research as the condition is complex, features a wide range of presentations and has yet to be defined by a single known cause although the existing body of research supports a diagnosis that considers combinations of genetic and environmental factors.
The organization further stated that any new treatment must undergo rigorous scientific testing and should be evaluated for its inherent benefits and risks before acceptance as a viable option.
“Our primary audience for this interim guidance was prescribing clinicians, and we have had a generally positive response from them,” Katharine Zuckerman, MD, Fellow of the American Academy of Pediatrics and member of the Council on Children with Disabilities, told Healio. “Many clinicians do not know what to do regarding family requests for leucovorin, so our interim guidance gives them additional information and a framework for decision making.”
In late September, the FDA announced it would begin the process of updating the label for leucovorin to include an indication for individuals with cerebral folate deficiency.
In its rationale, the FDA said that the move was made based on evidence that low levels of folate in the brain have been linked to developmental delays consistent with ASD.
As a result of the FDA’s stance, the AAP issued its own statement, alleging the FDA’s leucovorin decision as well as the HHS’s position on the relationship between Tylenol and risk for autism threatened the health of children by “spreading misleading information about vaccines, medications and the cause of autism.”
The AAP additionally said that it does not currently have prescribing guidelines for leucovorin for the indication of autism.
The organization instead urged clinicians and other health care professionals to prioritize harm mitigation if prescribing for children and to closely monitor patients for adverse effects while supporting families as they work through what may be complex therapeutic decisions.
“At this point we don’t know if leucovorin will be helpful or not to children with autism generally, so families and clinicians need to weigh the risks and benefits,” Zuckerman told Healio.
“The most clear indication for leucovorin use is for children with diagnosed cerebral folate deficiency, so pediatric clinicians may especially want to consider further investigation and leucovorin administration for children who meet that clinical profile,” she continued.
The effectiveness of leucovorin in treating children with ASD is unknown, Zuckerman said, as is its safety profile, particularly in long-term use. Side effects include irritability and allergic reactions, she added.
Leukovorin’s use also may mask other medical conditions, she said, and it may prompt families to abstain from other, more standard services and supports whose effectiveness are known.
“Benefits may possibly improve better communication outcomes, although this is uncertain, as it has not been substantiated in large-scale studies,” Zuckerman said.
Further, the AAP reiterated its support for research and innovation that can improve quality of life for autistic children and their families but affirmed its need for future developments with leucovorin or any other drug to be based in “both scientific rigor and respect for neurodiversity.”
“We would like to see at least one large, multicenter, randomized trial with clear enrollment criteria, pre-specified, objective endpoints and careful monitoring of adverse effects,” Zuckerman said. “We would hope that such a trial would be run by entities that do not have a personal or financial conflict of interest.”
She added that if such research provides new information regarding clinical benefit of the drug, the AAP would update its interim guidance.
For more information:
Katharine Zuckerman, MD, can be reached at psychiatry@healio.com.
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