The American Academy of Pediatrics (AAP) on Friday said it does not recommend the routine use of leucovorin for children with autism.
Calls for the professional association of pediatricians to provide guidance on leucovorin for autism emerged in September after U.S. health officials positioned the decades-old drug as a treatment for cerebral folate deficiency (CFD), which is present in some children with autism spectrum disorder (ASD).
As the FDA works with GSK to allow the British pharma’s previously discontinued leucovorin product Wellcovorin to treat CFD, the Department of Health and Human Services said in a Sept. 22 release that the move will “authorize treatment for children with ASD,” and that state Medicaid programs will be able to cover the drug for the indication of autism.
But in an “interim guidance” posted Friday, the AAP said “the current evidence base remains too limited to support” recommendations for the drug, suggesting that large clinical trials are needed to determine leucovorin’s efficacy and safety profile for the broader autism population. In its Sept. 22 release, the HHS said the National Institutes of Health will launch confirmatory trials and new research into the effects of leucovorin.
“The AAP does not have prescribing guidelines for leucovorin for the indication of autism,” the organization said.
In some children with autism, folate receptor alpha (FRα) autoantibodies block the transport of folate—a B vitamin—into the brain, leading to CFD. Leucovorin, or folinic acid, bypasses the defective folate transport system and delivers folate directly to the brain, according to an HHS fact sheet.
To back its decision on Wellcovorin, the FDA cited a “systematic analysis of literature published between 2009-2024, including published case reports with patient-level information, as well as mechanistic data.”
In a double-blind, placebo-controlled trial among 80 patients, researchers in India recorded better changes in Childhood Autism Rating Scale scores, as well as better changes in behavioral problems measured by the Child Behavior Checklist, for those who took leucovorin versus placebo. In the leucovorin group, improvement was more pronounced in children with higher levels of folate receptor autoantibodies.
The study was clearly too small, based on a recent Centers for Disease Control and Prevention estimate that in 2022, 1 in 31 children were diagnosed with autism by age 8 in the U.S.
The APP acknowledged that small studies have pointed to “potential benefit in carefully selected cases,” and that these “preliminary results are promising and have laid the groundwork for further investigation.”
The organization also said guidance needs “to be grounded in both scientific rigor and respect for neurodiversity.”
The doctors’ association previously blasted the Trump administration for linking autism to childhood vaccines and to the use of the pain reliever acetaminophen during pregnancy without evidence. It also criticized the administration for aggressively promoting leucovorin as an autism treatment.
Following a Sept. 22 White House press conference on autism, AAP President Susan Kressly, M.D., said in a statement that the event was “filled with dangerous claims and misleading information that sends a confusing message to parents and expecting parents and does a disservice to autistic individuals.”
“Don’t take Tylenol,” President Donald Trump repeatedly said during the Sept. 22 press conference, referring to the original Kenvue drug by its brand name.
But during an Oct. 29 event, U.S. Health Secretary Robert R. Kennedy Jr. said there’s no sufficient evidence to definitely link Tylenol to autism.
“The causative association… between Tylenol given in pregnancy and the perinatal periods is not sufficient to say it definitely causes autism. But it is very suggestive,” Kennedy said, as cited by Reuters.
“There should be a cautious approach to it,” he added.
Kenvue has pushed back against the claim by the Trump administration, having urged the FDA not to change the label of the popular pain medication over the uncorroborated link between its pregnancy use and autism.
Meanwhile, Texas Attorney General Ken Paxton has filed a new lawsuit against the Johnson & Johnson consumer health spinoff, alleging the company “deceptively” marketed Tylenol to pregnant women despite knowing exposure to the drug can cause a “significantly increased risk of autism and other disorders.”