Tylenol, Leucovorin, and Autism: What the Evidence Shows
At a Glance
- Tylenol in pregnancy: Research shows mixed findings; large sibling studies suggest family factors may explain much of the observed link to autism.
- Correlation vs. causation: Confounding by underlying illness or genetics complicates results; absolute risks remain small.
- Criticism of data: Some experts argue registry studies undercount acetaminophen use and may underestimate risks.
- Policy guidance: Health agencies still recommend Tylenol (paracetamol) as the safest option in pregnancy when used as directed.
- Leucovorin and autism: Small clinical trials suggest possible benefits for certain subgroups, but larger, more rigorous studies are needed.
Table of Contents
What the research says at a glance
Could Tylenol — the branded form of acetaminophen — contribute to autism spectrum disorder when used during pregnancy? And could leucovorin (folinic acid) improve communication or related skills for some people with autism? For related risks and supports at the intersection of autism and addiction, read our explainer on autism and alcohol abuse—where they overlap.
These questions have been explored for years, and they resurfaced after recent policy remarks. The scientific record contains signals and counter‑signals. Results vary because studies measure exposure differently, define outcomes in distinct ways, and enroll dissimilar populations. Taken together, the evidence is mixed rather than definitive. For practical guidance on safe use and misuse risks of over‑the‑counter pain relievers like acetaminophen, see our OTC overview.
Across many observational studies, prenatal acetaminophen exposure has sometimes been associated with a small increase in the odds of later diagnoses of autism or ADHD. Yet other analyses, especially those that account for family‑level factors, find the association weak or not statistically persuasive. For leucovorin, small clinical trials and pilot studies point to modest improvements in standardized measures for certain subgroups, though the data remain limited and heterogeneous.
A broad point frames the discussion: autism describes a wide spectrum of strengths and support needs. No single exposure or intervention is likely to have uniform effects across all individuals.
Causation, or just correlation?
Observational research can cover millions of people across long time spans, but it is vulnerable to confounding. A central concern here is “confounding by indication.” People take acetaminophen for fever, infection, migraines, or other pain. Those conditions, not the drug, might be linked to neurodevelopmental outcomes. If so, acetaminophen use would track with risk without being causal.
To probe this, a 2024 JAMA study examined 2.48 million births in Sweden. It leveraged a sibling‑comparison design: one pregnancy with acetaminophen exposure and a different pregnancy without exposure in the same family. Within families, the reported associations between prenatal acetaminophen and later diagnoses of autism, ADHD, or intellectual disability were greatly reduced. The authors concluded that shared genetic and environmental factors likely drive much of the crude association. For an overview of why ADHD and addiction often overlap—and what effective care looks like—see our primer.
That interpretation has been echoed by several groups. Brian Lee of Drexel University, a co‑author of the JAMA study, has emphasized that families with a higher inherited risk for autism or ADHD often report more headaches, infections, or pain during pregnancy — and therefore more acetaminophen use. That combination can manufacture an association even when the medication is not the cause.
Researchers have tested the question beyond family designs. Some studies measured acetaminophen‑related biomarkers in umbilical‑cord blood and linked those levels to later outcomes. Others used pharmacy and registry data to capture timing and dose. Across methods, when an association appears, its magnitude tends to be small; meta‑analyses often report relative increases of roughly 5%–20%, which would not explain broader changes in autism prevalence over time. Genetics also matters: risk most often reflects many interacting gene variants, complicating efforts to separate exposure from inherited vulnerability. As a contrast point, researchers cite stronger drug‑risk examples such as valproate exposure in pregnancy.
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Criticism of the Swedish sibling paper
Not all experts agree that the sibling evidence closes the case. A 2025 Environmental Health review evaluated 46 studies using the Navigation Guide framework and argued that the Swedish registry may undercount acetaminophen use. While surveys commonly find that about half of pregnant people take the drug at some point, only 7.5% had recorded use in the Swedish dataset. If many doses were missed, the sibling method could misclassify exposure and dampen a true signal. The authors, including Ann Z. Bauer and Andrea A. Baccarelli, also pointed to potential recall bias and differences in autism diagnosis across cohorts. They recommended cautionary language while calling for prospective studies with better exposure measurement and clearer separation of fever effects from medication effects.
Policy implications require balance. Recommending against acetaminophen would narrow options at a time when several alternative pain relievers have clearer fetal risks in late pregnancy. For a consumer‑friendly comparison of NSAIDs vs. acetaminophen (paracetamol), including when each is favored, see our guide.
Reflecting that balance, the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) states that paracetamol (acetaminophen) remains the recommended option in pregnancy when used as directed, and also notes that untreated pain and fever can themselves pose risks. Many clinical advisories stress using the lowest effective dose for the shortest necessary duration.
Safety note: combination analgesics such as hydrocodone/acetaminophen (Norco) contain acetaminophen—track total daily intake to avoid liver injury. The same caution applies to oxycodone/acetaminophen (Percocet); do not exceed labeled acetaminophen limits, especially if using multiple products.
There is common ground. Researchers on all sides endorse stronger exposure tracking, wider use of biomarkers, analytic strategies that address confounding by indication, and replication of results in diverse settings. These steps would narrow uncertainty and support clearer clinical guidance.
Does leucovorin help people with autism?
Leucovorin (folinic acid) is a form of vitamin B9 long used in oncology to “rescue” healthy cells after methotrexate. In neurology, it is given for cerebral folate deficiency. Some researchers propose that a subset of people with autism have problems transporting folate into the brain. If that is correct, high‑dose folinic acid might bypass the transport bottleneck and support gains in speech or social communication for that subgroup.
Clinical evidence exists but remains limited. A randomized, double‑blind, placebo‑controlled trial published in the European Journal of Pediatrics enrolled 80 children aged 2–10 years and followed them for 24 weeks. Participants received leucovorin or placebo in addition to ongoing therapies. The leucovorin group showed a small yet statistically significant improvement on a 60‑point autism severity scale, with supportive signals on some behavior checklists, and no serious adverse events were reported. The result suggests potential benefit but does not establish broad efficacy. Larger trials are needed.
Smaller studies, including open‑label designs, point in a similar direction but differ in inclusion criteria and outcomes. Because small trials can yield false positives and may not detect rare harms, the conventional next step would be multi‑center randomized trials with predefined biologic subgroups — for example, children with antifolate receptor antibodies or markers of cerebral folate deficiency. Outcomes should include practical measures such as functional communication, daily living skills, and quality of life, not only test scores.
Related reading: evidence and safety basics for aripiprazole (Abilify) for irritability in autism.
A practical obstacle is funding. Acetaminophen and leucovorin are inexpensive generics, leaving little commercial incentive for large, definitive trials or extensive observational work. Public and philanthropic support may therefore be essential to answer the questions that matter to patients, clinicians, and policymakers.
Bottom line: For acetaminophen in pregnancy, the overall evidence leans toward weak or non‑causal association sonce genetics and family factors are considered, though disagreement persists. For leucovorin, early trials suggest possible benefits for a biological subset but require replication at scale. Managing fever and pain in pregnancy, and evaluating targeted therapies for autism, remain important goals that depend on better evidence.
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FAQ: Tylenol, Leucovorin, and Autism — Evidence‑Based Answers
Is Tylenol (acetaminophen/paracetamol) safe during pregnancy?
Major health bodies state that paracetamol/acetaminophen remains the recommended first‑line pain/fever option in pregnancy when used as directed (lowest effective dose, shortest duration). This is reflected in recent statements from the WHO, the UK MHRA, and ACOG.
Does taking Tylenol while pregnant cause autism?
Current evidence does not show a causal link. A large 2024 JAMA study using sibling comparisons (≈2.5M births) found no increased risk of autism when controlling for family factors, and NIH summarized the same conclusion. Pediatric organizations likewise note no proven causal association.
How much Tylenol is safe to take when pregnant?
Follow the product label and your clinician’s advice; medical agencies emphasize using the lowest effective dose for the shortest time rather than a one‑size dose, because individual circumstances vary.
Should I avoid ibuprofen and other NSAIDs while pregnant?
Many NSAIDs are generally not recommended in pregnancy; regulators advise against swapping to NSAIDs and recommend paracetamol/acetaminophen as first choice when needed.
What did the Swedish sibling study (JAMA 2024) actually find?
In analyses comparing siblings differentially exposed to acetaminophen in utero, there was no increased risk of autism, ADHD, or intellectual disability (HRs ≈0.98–1.01), suggesting prior associations were largely due to shared familial factors.
Does prenatal acetaminophen raise the risk of ADHD?
In the same sibling‑comparison study, there was no increased ADHD risk after accounting for family confounding; pediatric groups likewise report no proven causal link.
Does leucovorin (folinic acid) help with autism symptoms?
Evidence is limited and mixed. Small randomized trials report modest improvements on some measures (e.g., language/communication), but results are not definitive and larger trials are needed. Media and academic summaries emphasize it is not a general treatment for all autistic individuals.
Who might benefit from leucovorin?
Some researchers focus on subgroups with cerebral folate deficiency or folate receptor‑alpha autoantibodies; reviews and clinical commentary suggest any benefit may be subgroup‑specific and should be guided by specialist care.
What do global and national authorities say right now?
WHO and MHRA say there’s no conclusive evidence that paracetamol in pregnancy causes autism and continue to recommend it as first‑line when used as directed; ACOG’s advisory aligns with that stance. FIGO likewise states current evidence does not support a causal association.
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Medical Disclaimer
The information on this page is intended for educational purposes only and should not be used as a replacement for professional medical advice, diagnosis, or treatment. Medications such as Tylenol (acetaminophen), leucovorin, or any other prescription or over-the-counter drug should only be taken under the guidance of a licensed healthcare provider. Do not begin, change, or stop any medication without first consulting your doctor. If you are experiencing severe side effects, withdrawal symptoms, or thoughts of self-harm, call 911 in the United States or seek immediate medical assistance. For mental health support, dial 988 to connect with the Suicide & Crisis Lifeline, available 24/7.
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- Ahlqvist, V. H., et al. (2024). Acetaminophen use during pregnancy and children’s risk of autism, ADHD, and intellectual disability. JAMA, 331(14), 1205–1214. https://doi.org/10.1001/jama.2024.3172. Accessed September 29, 2025.
- Prada, D., et al. (2025). Evaluation of the evidence on acetaminophen use and neurodevelopmental disorders: A systematic review using the Navigation Guide methodology. Environmental Health.https://ehjournal.biomedcentral.com/articles/10.1186/s12940-025-01208-0. Accessed September 29, 2025.
- U.S. Food and Drug Administration. (2025, Sept. 22). FDA responds to evidence of possible association between autism and acetaminophen use during pregnancy. https://www.fda.gov/news-events/press-announcements/fda-responds-evidence-possible-association-between-autism-and-acetaminophen-use-during-pregnancy. Accessed September 29, 2025.
- U.S. Food and Drug Administration. (2025, Sept. 22). Notice to physicians on the use of acetaminophen during pregnancy. https://www.fda.gov/media/188843/download. Accessed September 29, 2025.
- American College of Obstetricians and Gynecologists. (2025, Sept.). Acetaminophen use in pregnancy and neurodevelopmental outcomes. Practice Advisory. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2025/09/acetaminophen-use-in-pregnancy-and-neurodevelopmental-outcomes. Accessed September 29, 2025.
- Panda, P. K., et al. (2024). Efficacy of oral folinic acid supplementation in children with autism spectrum disorder: A randomized double-blind, placebo-controlled trial. European Journal of Pediatrics.https://pubmed.ncbi.nlm.nih.gov/39243316/. Accessed September 29, 2025.
- Frye, R., et al. (2018). Folinic acid improves verbal communication in children with autism and language impairment: A randomized double-blind placebo-controlled trial. Molecular Psychiatry. https://www.nature.com/articles/mp2016168. Accessed September 29, 2025.
- Renard, E., et al. (2020). Folinic acid improves the score of autism in the EFFET randomized trial. PubMed.https://pubmed.ncbi.nlm.nih.gov/32387472/. Accessed September 29, 2025.
- Zhang, C., et al. (2025). Safety and efficacy of high-dose folinic acid in children with autism: The impact of folate metabolism gene polymorphisms. Nutrients, 17(9), 1602. https://www.mdpi.com/2072-6643/17/9/1602. Accessed September 29, 2025.
- International Federation of Gynecology and Obstetrics (FIGO). (2025). Paracetamol (acetaminophen) use during pregnancy and autism risk: Evidence does not support causal association. https://www.figo.org/paracetamol-acetaminophen-use-during-pregnancy-and-autism-risk-evidence-does-not-support-causal. Accessed September 29, 2025.
- Oxford University Hospitals. (2025, Sept.). No evidence that paracetamol use in pregnancy causes autism spectrum disorder. https://www.wrh.ox.ac.uk/news/no-evidence-that-paracetamol-use-in-pregnancy-causes-autism-spectrum-disorder. Accessed September 29, 2025.
- Autism Speaks. (2024, Apr.). Research shows no causal link between Tylenol and autism. https://www.autismspeaks.org/science-news/tylenol-and-autism. Accessed September 29, 2025.
- Autism Speaks. (2025, Sept.). Autism Speaks statement on Tylenol and leucovorin. https://www.autismspeaks.org/news/autism-speaks-statement-tylenol-and-leucovorin. Accessed September 29, 2025.
- Yale School of Public Health. (2025, Sept.). What the research says about autism and Tylenol use during pregnancy. https://ysph.yale.edu/news-article/what-the-research-says-about-autism-and-tylenol-use-during-pregnancy. Accessed September 29, 2025.
- National Institute of Neurological Disorders and Stroke. (2024, Apr.). Study reveals no causal link between neurodevelopmental disorders and acetaminophen exposure at birth. https://www.ninds.nih.gov/news-events/news/press-releases/study-reveals-no-causal-link-between-neurodevelopmental-disorders-and-acetaminophen-exposure-birth. Accessed September 29, 2025.
