FDA Announces Label Changes for Acetaminophen in Pregnancy, Approves Leucovorin Calcium for CFD

On September 22, 2025, 5he US Food and Drug Administration (FDA) announced a pair actions of relevance to pediatric clinicians: initiation of a label change process for acetaminophen (Tylenol and similar products) based on evidence suggesting an association between prenatal exposure and increased risk of neurodevelopmental disorders, andapproval of leucovorin calcium (Wellcovorin; GSK) for the treatment of cerebral folate deficiency (CFD), a rare neurological disorder associated with autistic features, seizures, and movement abnormalities. ^1,2,3

Acetaminophen Use in Pregnancy

"The FDA is taking action to make parents and doctors aware of a considerable body of evidence about potential risks associated with acetaminophen. Even with this body of evidence, the choice still belongs with parents," explained FDA Commissioner Marty Makary, MD, MPH, in the statement.

The FDA cited evidence from multiple large-scale cohort studies, including the Nurses’ Health Study II and the Boston Birth Cohort, demonstrating a correlation between maternal acetaminophen use during pregnancy and subsequent diagnoses of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in offspring.

While not establishing causality, these studies suggest a relative risk increase of approximately 20% to 30%. The association appears most pronounced with chronic use extending across pregnancy.

For pediatricians, these developments are clinically relevant in anticipatory guidance. Children with suspected or confirmed prenatal acetaminophen exposure may merit closer developmental surveillance, particularly if exposures were prolonged.

While causation has not been proven, pediatricians may face parental questions regarding exposure history and should emphasize that acetaminophen remains the only over-the-counter antipyretic deemed acceptable during pregnancy, especially as untreated maternal fever itself is a known risk factor for adverse neurodevelopmental outcomes.

"The precautionary principle may lead many to avoid using acetaminophen during pregnancy, especially since most low-grade fevers do not require treatment. It remains reasonable, however, for pregnant women to use acetaminophen in certain scenarios," Makary added.

Leucovorin Calcium for Cerebral Folate Deficiency

The FDA also approved leucovorin calcium tablets for the treatment of CFD.² This condition results from impaired transport of folate into the central nervous system and has been associated with developmental delays, autistic behaviors, seizures, and impaired motor coordination.²

The FDA conducted a systematic review of published literature from 2009 to 2024, including mechanistic data and patient-level case reports, and determined that evidence supports the efficacy of leucovorin calcium in this population.² “We have witnessed a tragic 4-fold increase in autism over 2 decades. 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," Makary said.

Case reports of genetically confirmed CFD identified by the FDA will be incorporated into US prescribing information. George Tidmarsh, MD, PhD, director of the FDA’s Center for Drug Evaluation and Research, described the effort as reflective of the agency’s commitment to repurposing existing drugs for chronic neurological conditions.²

For pediatricians, the approval of leucovorin calcium represents an additional therapeutic option in confirmed CFD. However, the FDA emphasized that evidence remains limited for broader populations, such as children with folate receptor α autoantibodies and neuropsychiatric features, and additional research is needed to clarify safety and efficacy.²

Clinical Implications

For pediatricians, these FDA actions are notable both for surveillance and for potential therapy. Developmental monitoring in children with prenatal acetaminophen exposure should remain part of anticipatory guidance, with reassurance to families that causality remains unproven. The approval of leucovorin calcium for CFD offers a new evidence-based intervention, though its application should remain focused on patients with confirmed diagnoses until additional data are available.

Editor's Note: Artificial Intelligence was used in the creation of this content.

References

1. US Food and Drug Administration. FDA Responds to Evidence of Possible Association Between Autism and Acetaminophen Use During Pregnancy. September 22, 2025. Accessed September 22, 2025. https://www.fda.gov/news-events/press-announcements/fda-responds-evidence-possible-association-between-autism-and-acetaminophen-use-during-pregnancy
2. US Food and Drug Administration. FDA Takes Action to Make a Treatment Available for Autism Symptoms. September 22, 2025. Accessed September 22, 2025. https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms
3. GSK. GSK to Submit Label Update for Wellcovorin (Leucovorin) at US FDA’s Request. September 22, 2025. Accessed September 22, 2025. https://www.gsk.com/en-gb/media/press-releases/gsk-to-submit-label-update-for-wellcovorin-leucovorin-at-us-fda-s-request/