Autism experts sharply criticized a report from the Trump administration that claims prenatal acetaminophen use and vaccines may increase the risk for autism and that a drug pulled from the market 25 years ago can treat symptoms of the disorder.

In a press briefing late Monday, the administration urged pregnant women to avoid acetaminophen and announced plans to re-approve leucovorin calcium tablets (Wellcovorin, GSK) for patients with symptoms of autism and cerebral folate deficiency (CFD), a neurological condition that has been associated with autism.

“The [US] FDA is responding to clinical and laboratory studies that suggest a potential association between acetaminophen used during pregnancy and adverse neurodevelopmental outcomes, including later diagnosis for ADHD [attention-deficit hyperactivity disorder] and autism,” US Department of Health and Human Services (HHS) Secretary Robert F. Kennedy, Jr, said during the briefing.

Several autism experts said the studies Kennedy mentioned were not scientifically rigorous and did not support a link between autism and acetaminophen or the claim that leucovorin is an effective treatment for autism.

The Trump administration “backed itself into a corner by saying that we will know the causes of and treatment for autism by September. Now they are relying on faulty data and weak evidence to implicate acetaminophen as a cause and leucovorin as a cure,” David S. Mandell, ScD, member of the executive committee of the Coalition of Autism Scientists, told Medscape Medical News.

“Pregnant women have few safe, over-the-counter options available to them to treat pain and inflammation. Acetaminophen is one. Not using it judiciously and when needed may actually increase risks to pregnant women and their babies,” said Mandell, professor and director of the Penn Center for Mental Health at the University of Pennsylvania Perelman School of Medicine, Philadelphia.

Acetaminophen Safe During Pregnancy

While a recent summary analysis of 46 relevant studies found some evidence for a weak association with autism risk and use of acetaminophen, a more recent and rigorous study from Sweden published in JAMA found that acetaminophen did not cause autism.

The Swedish study of 2.4 million children (1995-2019) that included sibling data to control for genetic and environmental factors found no relationship between exposure to acetaminophen in utero and subsequent occurrence of autism, ADHD, or intellectual disability. This suggests no causal effect of acetaminophen in autism.

Those and other findings show that prenatal acetaminophen use is safe, the American Psychiatric Association (APA) said in a statement.

“A strong base of evidence shows that acetaminophen, when taken as directed, is safe for use during pregnancy. Any decisions around a course of treatment should be determined by a patient and their doctor,” the APA said.

Kennedy said the FDA will issue a “physician’s notice” about the risk of acetaminophen use during pregnancy and begin the process to initiate a safety label change to reflect evidence suggesting that use of acetaminophen by pregnant women may be associated with an increased risk for autism and ADHD in children.

Still, Kennedy said HHS “encourages clinicians to exercise their best judgment and use of acetaminophen for fevers and pain in pregnancy by prescribing the lowest effective dose for the shortest necessary duration and only when treatment is required.”

‘Zero’ Odds of a Single Cause for Autism

Administration officials also announced a program to fund research into the causes of autism, including an investigation into the disproven link between vaccines and autism risk.

“We are continuing to investigate a multiplicity of potential causes with no areas of taboo. One area that we are closely examining, as the President mentioned, is vaccines,” Kennedy said during the briefing.

As reported by Medscape Medical News, the administration announced plans last week to award a research contract to study the association between autism risk and vaccines, a move that raised concerns among autism experts.

The APA echoed those concerns and called for the administration to focus on proven science.

“It is essential that the administration prioritizes evidence-based support for individuals on the autism spectrum and invests in long-term comprehensive research about the disorder. Vaccines do not cause autism. Claims of any such association have been repeatedly discredited in peer-reviewed studies,” the APA said in the statement.

Experts agree that autism is a complex neurodevelopmental condition influenced by many genetic and environmental factors, with no known single cause.

Because autism is so complex, “the odds of identifying a single factor that causes autism, whether genetic or environmental, is zero,” Alexander Kolevzon, MD, clinical director of the Seaver Autism Center at Mount Sinai in New York City, noted in an interview with Medscape Medical News earlier this year.

Label Update for Leucovorin

Kennedy also said his agency has identified leucovorin calcium as “an exciting therapy” that may benefit children with autism and has asked the manufacturer GSK to submit a supplemental New Drug Application to update the label for that indication.

The FDA originally approved the drug in 1983 for the treatment of folic acid deficiency and megaloblastic anemia but withdrew its approval in 1999 after GSK removed the drug from the market following the release of a generic version.

The FDA has published a notice in the Federal Register outlining a label update for leucovorin for CFD.

In calling for the drug to be re-approved, the agency pointed to case reports with more than 40 adult and pediatric patients with CFD who showed symptom improvement following treatment with oral leucovorin.

“This action establishes the first FDA-recognized therapeutic for children with cerebral folate deficiency and autistic symptoms,” HHS said in a statement.

The change will authorize treatment of children with autism spectrum disorder (ASD), with continued use if children show language, social, or adaptive gains. Following the label update for ASD, state Medicaid programs will be able to cover leucovorin for the indication of ASD, in partnership with the Centers for Medicare & Medicaid Services.

HHS said the National Institutes of Health will launch confirmatory trials and new research into the impact of leucovorin including safety studies.

New Indication Is Premature

Autism experts worry that this action is premature and that the evidence supporting leucovorin as a treatment for autism is weak.

“There are only a handful of clinical trials of leucovorin, and evidence connecting treatment to improvements in outcomes is very weak. All of them are very small, and the study designs and approaches to statistical analyses of the data are not all of high quality,” the Coalition of Autism Scientists said in a statement to Medscape Medical News.

A coalition spokesperson said scientists reviewed five published studies on leucovorin for autism and found that these lacked high-quality study designs or statistical analyses. Therefore, the group said it does not support any recommendation regarding increased use of leucovorin.

“It is premature to say that leucovorin is an effective treatment for autism, and saying so will mislead and raise false hopes for families. A large, rigorous, and independent clinical trial is needed before such a claim can be made,” the statement continued.

They called for a “well-designed, large-scale clinical trial of leucovorin with all of the rigor needed (biomarkers, proper endpoints) and, most importantly, a preregistered analysis plan.”