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Autism, Acetaminophine, Folinic Acid. Research Continues – What Parents Will Want to Know
The U.S. Food and Drug Administration today initiated the process for a label change for acetaminophen (Tylenol and similar products) to reflect evidence suggesting that the use of acetaminophen by pregnant women may be associated with an increased risk of neurological conditions such as autism and ADHD in children. The agency also issued a related letter alerting physicians nationwide.
“The FDA is taking action to make parents and doctors aware of a considerable body of evidence about potential risks associated with acetaminophen,” said FDA Commissioner Marty Makary, M.D., M.P.H. “Even with this body of evidence, the choice still belongs with parents. The precautionary principle may lead many to avoid using acetaminophen during pregnancy, especially since most low-grade fevers don’t require treatment. It remains reasonable, however, for pregnant women to use acetaminophen in certain scenarios.”
Evidence in recent years has suggested a correlation between acetaminophen use during pregnancy and subsequent diagnosis of conditions like autism and ADHD. Multiple large-scale cohort studies, including the Nurses’ Health Study II and the Boston Birth Cohort, find this association. Some studies have described that the risk may be most pronounced when acetaminophen is taken chronically throughout pregnancy.
It is important to note that while an association between acetaminophen and neurological conditions has been described in many studies, a causal relationship has not been established and there are contrary studies in the scientific literature. It is also noted that acetaminophen is the only over-the-counter drug approved for use to treat fevers during pregnancy, and high fevers in pregnant women can pose a risk to their children. Additionally, aspirin and ibuprofen have well-documented adverse impacts on the fetus.
FDA Statement on Treatment with Leucovorin:
The U.S. Food and Drug Administration today initiated the approval of leucovorin calcium tablets for patients with cerebral folate deficiency (CFD), a neurological condition that affects folate (a vitamin essential for brain health) transport into the brain. Individuals with cerebral folate deficiency have been observed to have developmental delays with autistic features (e.g., challenges with social communication, sensory processing, and repetitive behaviors), seizures, and problems with movement and coordination.
The FDA has conducted a systematic analysis of literature published between 2009-2024, including published case reports with patient-level information, as well as mechanistic data, and has determined that the information supports a finding that leucovorin calcium can help individuals suffering from CFD.
“We have witnessed a tragic four-fold increase in autism over two decades,” said FDA Commissioner Marty Makary, M.D., M.P.H. “Children are suffering and deserve access to potential treatments that have shown promise. We are using gold standard science and common sense to deliver for the American people.”
The FDA is working with GSK, the innovator of Wellcovorin (leucovorin calcium), on a process to include the essential scientific information needed for the safe and effective use of these drug products for adults and pediatric patients with CFD. As the New Drug Application (NDA) holder for this medicine, GSK has preliminarily agreed to work with the FDA on this relabeling effort.
“The FDA is collaborating with GSK to broaden the existing Wellcovorin label,” said George Tidmarsh, M.D., Ph.D., Director of the FDA’s Center for Drug Evaluation and Research. “This effort reflects the FDA’s commitment to identify opportunities to repurpose drugs to treat chronic diseases. The FDA remains committed to finding and treating the root causes of autism.”
CFD has also been reported in a broader patient population with neuropsychiatric symptoms, including autistic features, and detectable serum autoantibodies to the folate receptor alpha; however, there are limitations on the available data for the use of leucovorin in this population and additional studies are needed to assess safety and efficacy.
More information from the FDA, HERE
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Statement of Health & Human Services:
Autism Announcement Fact Sheet
Today, President Trump held a press conference in the Roosevelt Room to announce progress in uncovering the root causes of autism, as promised by HHS Secretary Kennedy. The three announcements made today include: leucovorin as a promising treatment for symptoms of autism, a notice to physicians on the use of acetaminophen, and an announcement of recipients of the NIH Autism Data Science Initiative.
Autism Prevalence in the United States
Key Findings
- 1 in 31 U.S. children (3.2%) born in 2014 are diagnosed with autism spectrum disorder (ASD).
- Sharp increase from 1 in 36 just two years earlier.
- Prevalence nearly 5 times higher than when the CDC began tracking in 2000 (1 in 150).
- Boys disproportionately affected: 1 in 20 (5%).
- California highest prevalence: 1 in 12.5.
Source: Centers for Disease Control and Prevention (CDC), Morbidity and Mortality Weekly Report (MMWR), Surveillance Summaries, Vol. 74, No. SS-2, April 2025
Read the full CDC study
Leucovorin for Cerebral Folate Deficiency
The Condition: Cerebral Folate Deficiency (CFD)
- What it is: A neurological condition where the brain doesn’t get enough folate (an essential B-vitamin), even when folate levels in the rest of the body are normal. Folate is essential for brain development and function. Deficiency of folate in the brain causes severe problems including autistic symptoms.
- Who it affects: CFD has multiple causes, including rare genetic forms and autoimmune forms, with the latter being more common. FOLR1 deficiency is a rare genetic form which may affect 1 in 1,000,000 individuals worldwide; however, the true prevalence is unknown. CFD presents in early childhood with severe neurological symptoms and developmental delay. Autoimmune forms are caused by autoantibodies that mistakenly attack the body’s folate transport system, preventing folate from reaching the brain and yielding the same severe symptoms.
- Symptoms: Patients with genetic forms have symptoms, typically beginning around age 2, such as global developmental delays with autistic features and psychomotor regression, intractable seizures, and motor disorders. Patients with autoimmune forms have heterogeneous neuropsychiatric symptoms, including potentially severe autism features.
The Treatment: Leucovorin (Folinic Acid)
- What it does: Leucovorin bypasses the defective folate transport system and delivers the active form of folate directly to the brain.
- Current evidence and treatment response: Analysis across 23 publications from 2009-2024 demonstrated the effectiveness for CFD. Overall, 85% of patients experienced some type of clinical benefit including improved speech/communication capabilities. Efficacy data on the use of leucovorin in the autoimmune form of CFD suggest that these patients may also benefit from treatment; however, the data are limited and need to be replicated.
- Safety profile: Leucovorin is generally well-tolerated based on available data obtained over 40 years of use for other conditions. The safety in CFD patients appears consistent with leucovorin’s established safety profile in these other approved indications.
Context
- Population impact: While the most common FOLR1 gene mutation is rare, it is a proven cause of this devastating but potentially treatable presentation of autistic symptoms. Leucovorin’s use in patients with autoimmune CFD could potentially have a larger impact on the U.S. population; however additional studies are needed. Usage data from the FDA has shown that off-label use of leucovorin has increased significantly due to growing awareness among the autism community. Ingesting more folate through over-the-counter supplements is not indicated and could be harmful.
- Regulatory considerations: The original NDA for leucovorin was approved in 1983 but withdrawn in 1999 when GlaxoSmithKline (GSK) stopped marketing the product after the entry of generic versions into the market. This withdrawal was not for safety or effectiveness reasons. Following review of the data from patients with genetically confirmed CFD who showed profound symptom improvement with oral leucovorin treatment, the FDA has announced that they are requesting from the innovator company updated prescribing information (PI) to include the new indication of CFD, a condition often associated with autistic symptoms. The PI of generic leucovorin products will be updated accordingly.
- Research landscape: The evidence base for efficacy of leucovorin in genetic forms of CFD consists entirely of case reports and case series due to the condition’s rarity. However, the FDA has worked with the NIH to review the scientific evidence for its use in autoimmune forms, particularly in cases manifesting with clinical features of autism spectrum disorder (ASD). The NIH is committed to supporting follow-up research to understand the impact of the label change and the potential broader benefit in individuals with ASD, and to working with FDA and CMS on post-market surveillance and safety studies.
Acetaminophen Use in Pregnancy
The Condition: Acetaminophen Exposure in Utero
- What it is: Acetaminophen (Tylenol) is an over-the-counter analgesic and antipyretic widely used during pregnancy. Concerns have arisen regarding possible neurodevelopmental risks associated with chronic prenatal exposure and potential overuse for low-grade fevers in pregnant women.
- Who it affects: Chronic acetaminophen use in pregnant women, especially late in pregnancy, may cause long-term neurological effects in their children.
- Evidence base: Large-scale cohort studies, including the Nurses’ Health Study II and the Boston Birth Cohort, report associations between in utero exposure and later diagnoses of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Scientists have proposed biological mechanisms linking prenatal acetaminophen exposure to altered brain development.
- Conflicting findings: Family-based Scandinavian studies, comparing exposed and unexposed siblings, have not shown significant associations. Critics from Icahn School of Medicine at Mt. Sinai and Harvard argue that statistical adjustments in these analyses may mask true effects.
Clinical Considerations: Chronic Use of Acetaminophen During Pregnancy
- What it does: Acetaminophen is the only over-the-counter medication considered safe for treating fever during pregnancy. Maternal fever itself carries risks, including neural tube defects and preterm birth.
- Current evidence and recommendations: Evidence does not definitively establish causality, but the consistent associations raise concern. An international consensus statement (2021) recommends pregnant women minimize use, consult providers before long-term use, and apply the lowest effective dose for the shortest duration.
- Safety profile: When used short-term and at appropriate dosages, acetaminophen remains widely regarded as safe. However, unresolved questions remain regarding chronic or late-pregnancy exposure.
Context
- Population impact: Because acetaminophen is one of the most common medications taken during pregnancy, even a modest increase in risk could have a significant public health impact.
- Balancing risks: Experts emphasize a balanced approach, acknowledging potential risks of acetaminophen exposure while recognizing the dangers of untreated maternal fever and pain.
- Research landscape: Randomized trials of drug exposure during pregnancy are generally infeasible. Thus, continued reliance on epidemiologic studies, mechanistic research, and meta-analyses will shape guidance moving forward.
More information on research – HERE
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From Harvard Public Health:
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Autism Speaks Announcement following White House event:
Autism Speaks statement on Tylenol and leucovorin
Women who are pregnant and families considering new therapies for autism should always consult with their doctor.
While some observational studies have suggested possible associations between Tylenol (also known as acetaminophen) and autism, it is important to note that they have not – to date – proven causation, which we know to be influenced by many other factors such as genetics, parental health and environment.
As highlighted in today’s announcement, leucovorin shows promise in improving speech in minimally verbal children. However, larger, well-controlled clinical trials are still needed to confirm its efficacy and safety as a therapeutic treatment.
At Autism Speaks, we have been encouraged by the recent, increased focus on autism and have consistently advocated for substantive spending on the research and services needed to improve the lives of autistic people. We acknowledge today’s commitment and the investment being directed toward further research and resources, and express our sincere hope that these efforts will translate into true, improved quality of life for those with autism.
We urge the Administration’s resources be dedicated toward advancing new and innovative areas of research, so the community benefits from fresh insights, rather than revisiting questions that have been well studied, including vaccines and autism. We look forward to continuing our bipartisan work and supporting public officials, as well as the medical and scientific communities in their efforts to improve the lives of those on the spectrum.
More information, HERE
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NOTE: Questions about Ibuprofin, or a product such as Motrin, have been raised, and not addressed by this current announcement. However, what we know: “Because of known fetal risks, ibuprofen is usually not recommended during certain periods of pregnancy (for example, after 20 weeks). The risks that are known are of a different nature (fetal cardiovascular, kidney, etc.), not confirmed neurodevelopmental disorders.
It is important to make decisions in an informed way, and with your physician.
This is a developing story.
The real answer as to why we are seeing more cases of autism is probably simple: increased attention and improved detection methods. A number of studies back up this hypothesis:
https://pmc.ncbi.nlm.nih.gov/articles/PMC2800781/
https://publichealth.jhu.edu/2025/is-there-an-autism-epidemic#:~:text=Changes%20in%20the%20diagnostic%20criteria,better%20screening%2C%20and%20increased%20awareness.
https://www.scientificamerican.com/article/the-real-reasons-autism-rates-are-up-in-the-u-s/#:~:text=Awareness%20and%20changing%20criteria%20probably,survive%20now%20than%20ever%20before.
https://www.science.org/content/article/autism-rates-are-it-really-rise
https://www.peacehealth.org/healthy-you/why-do-autism-diagnoses-seem-more-common-now
https://neurodivergentinsights.com/rise-in-autism-diagnoses/?srsltid=AfmBOor7ZtXD48CiFAbYF-EYJmoY3phAOyuQNwUGJOvrcXNrHscRYiyR
https://www.thetransmitter.org/spectrum/rising-awareness-may-explain-spike-in-autism-diagnoses/
https://www.statnews.com/2023/03/23/autism-epidemic-cdc-numbers/
The simple truth probably is, there is no epidemic of autism. There is an epidemic of awareness and need. The diagnosis is more common, but the actual condition does not appear to be.
People are looking for a villain or a scapegoat as being ‘responsible’ partly because that might suggest there’s a simple, magical ‘cure.’ Unfortunately, as with most things in biology, it’s not that simple. The overwhelming body of bona fide scientific data show that neither vaccines nor acetaminophen are ‘causing’ autism. As much as everyone would love to find a straightforward ‘cure’ it won’t be as easy as that.
As always, we encourage everyone to read everything, and talk to the professionals on a case to case basis – we can only make our own – and prudent – decisions. Just as many feel the anti-Tylenol argument, long in the literature as it has been, receives so much pushback because of economic and commerce concerns, one can make the same argument about the over-diagnosis – many commerce reasons to put that label on, change the label, fund all the special services and program. Is something happening to our children when we see, up close and personal, behavioral issues that are resistant to treatment, almost of any kind? Just as we are about allergies to peanuts – out of the blue. And what has been the “goes against all reason” treatment – that is working? Using peanut butter! Science is ever-changing…and what we never think would be one day – becomes nearly mainstream the next. Thanks, Nick for your information. We suggest we read those links!
HOW DOES THE US COMPARE WITH OTHER COUNTRIES?
One example given was in Cuba – where Tylenol is not available and they have almost no cases of autism. But! Is it a diagnosis issue or something connected to environment or no acetaminophen? The Amish, in the US, have almost no cases of autism, neither do they use most vaccines or medicines – again, they are fairly cloistered, so… It is also well known that the US gives more vaccines than most countries in the world. While some question the commerce mission of promotion of Tylenol and vaccines, others question the commerce behind diagnoses, too. Clearly more research is called for. Overall recommendation with tylenol would be take it only if you need it – under a physician’s guidance, and only as much and as long as you need to. That’s pretty basic. Of course, prenatal care is essential and medication decisions should be made in discussion with one’s doctor.
It’s important to distinguish between correlation and causation. People eat more ice cream in the summer. People also get more sunburns and shark attacks in the summer. It doesn’t mean eating ice cream causes sunburn or being attacked by a shark. It’s just a correlation, not a causation.
Autism is a terrible thing in children who have it, but baselessly scapegoating something which is not a cause won’t help anyone. It is *far* from proven that acetaminophen ’causes’ autism.
On the other hand, bona fide scientific studies have shown a link between fevers during pregnancy and autism in children:
https://pmc.ncbi.nlm.nih.gov/articles/PMC7784630/
How many cases of autism might result because a pregnant woman may decline to take acetaminophen for a fever?
Likewise, the purported ‘cure’ leucovorin *might* be useful in cases of vitamin deficiency, but it has only been studied in a few dozen people.
As Neil deGrasse Tyson said, “The good thing about science is that it’s true whether or not you believe in it.”
Ignore real, bona fide scientific evidence, and believe unfounded quackery at your own risk.
The overwhelming need for more research is clear
Neil used to be the questioner, not so much these days. Saw an interview with him recently. I always opt for more information, and put trust in each person to weigh the options, with their MD. The Harvard study backs up some of the Tylenol questions, but much more needs to be learned.
There have been seven large-scale, rigorous epidemiological studies assessing whether prenatal acetaminophen and autism are linked, noted David Mandell, ScD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.
“One finds an effect and six find no effect, It is really challenging to separate out the effect of Tylenol from the effect of the infections that may lead people to take Tylenol,”
“It’s hard to understand why the Trump administration has picked Tylenol as their huge big finding,” said Helen Tager-Flusberg, PhD, of Boston University, founder of the Coalition of Autism Scientists, an autism health policy group.
“Number one, if there is an association between Tylenol and autism, it’s a very minor association. There’s no genuine causal link here. The studies that have investigated this that have been well-controlled demonstrate clearly that in small doses, appropriate for the level of infection or fever or pain, really do not contribute risk for autism,”