More than half of pregnant women worldwide use paracetamol, often because it has been considered safer than other painkillers that carry known risks of miscarriage or birth defects. This widespread reliance makes the new findings particularly significant for global public health policy.
Published Sep 01, 2025 | 7:00 AM ⚊ Updated Sep 01, 2025 | 7:00 AM
Paracetamol (Creative Commons)
Synopsis: The use of acetaminophen (paracetamol) by pregnant women has been strongly linked to an increased risk of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit/hyperactivity disorder in children, according to a comprehensive review of 46 studies published in Environmental Health. The analysis found that the strongest and most rigorously designed studies were more likely to show harmful associations, particularly with exposure during the second and third trimesters.
The widespread use of acetaminophen, better known as paracetamol, as a pain relief medication among pregnant women has been strongly linked to neurodevelopmental disorders in children, according to a new analysis of 46 high-quality studies involving hundreds of thousands of mother-child pairs across multiple countries.
The paper, published in the journal Environmental Health, found consistent evidence linking the world’s most commonly used pain and fever medicine during pregnancy to disorders such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in children.
Of the 46 studies reviewed, 27 showed a significant link between prenatal acetaminophen use and neurodevelopmental disorders, while nine found no link and four suggested a possible protective effect. Crucially, the strongest and most carefully designed studies were more likely to demonstrate harmful associations.
The findings challenge the long-held perception that acetaminophen is the safest pain relief option for pregnant women.
More than half of pregnant women worldwide use acetaminophen, often because it has been considered safer than other painkillers that carry known risks of miscarriage or birth defects. This widespread reliance makes the new findings particularly significant for global public health policy.
“Our findings show that higher-quality studies are more likely to show a link between prenatal acetaminophen exposure and increased risks of autism and ADHD,” said Dr Diddier Prada, Assistant Professor of Population Health Science and Policy, and Environmental Medicine and Climate Science at the Icahn School of Medicine at Mount Sinai.
“Given the widespread use of this medication, even a small increase in risk could have major public health implications.”
The study, led by researchers from Harvard, UCLA, and the Icahn School of Medicine at Mount Sinai, represents the first application of the rigorous Navigation Guide methodology to systematically evaluate the scientific literature on this issue.
The methodology is a gold-standard framework for synthesising and evaluating environmental health data. It allows researchers to assess each study’s risk of bias, such as selective reporting or incomplete data, and to evaluate the strength of evidence and quality of studies individually and collectively.
The researchers noted a troubling pattern in their analysis: “Our analysis demonstrated evidence consistent with an association between exposure to acetaminophen during pregnancy and offspring with NDDs, including ASD and ADHD, though observational limitations preclude definitive causation.”
They emphasised that while population-level trends in neurodevelopmental disorder rates have risen potentially due to several factors including improved diagnostics, “a causal relationship is plausible because of the consistency of the results and appropriate control for bias in the large majority of the epidemiological studies.”
The timing of exposure appears particularly important. Studies that provided detailed timing data showed stronger associations with exposure during the second and third trimesters, suggesting specific windows of heightened vulnerability during foetal brain development.
The study goes beyond statistical associations to explore biological mechanisms that could explain the connection between acetaminophen use and neurodevelopmental disorders. These mechanisms provide scientific plausibility for the observed associations.
Acetaminophen readily crosses the placental barrier, reaching levels in foetal circulation similar to maternal circulation within less than an hour of ingestion. Once in the foetal system, the drug undergoes oxidative metabolism via the enzyme CYP2E1, present in foetal brains, placenta, and lungs, producing toxic metabolites that may damage developing neural tissue.
The developing brain is particularly vulnerable to such damage because it is rapidly growing and requires significant energy metabolism, making it highly susceptible to oxidative stress. Animal studies have shown that prenatal acetaminophen exposure increases oxidative stress markers in the foetal brain and is associated with measurable neurodevelopmental deficits.
Additionally, acetaminophen affects prostaglandin and endocannabinoid pathways, which play crucial roles in prenatal neuronal development. The drug also acts as an endocrine disruptor, interfering with hormone-dependent processes essential for healthy brain development, potentially altering steroidogenesis in the placenta and inducing placental damage.
Perhaps most concerning are the epigenetic effects – changes in gene expression that do not alter the underlying DNA sequence but can have lasting impacts on development. During prenatal growth, the epigenome undergoes dynamic changes that regulate gene expression and contribute to proper brain development.
Research has shown that prenatal acetaminophen use is associated with DNA methylation changes in foetal tissues and the placenta, including at locations vital for neurodevelopment. Similar changes have been observed in children diagnosed with ADHD who were exposed to prenatal acetaminophen, with studies suggesting DNA methylation alterations in genes involved in oxidative stress, neural transmission, and sensory pathways.
“Alterations in the epigenome can alter neural networks critical for normal brain function, resulting in abnormal gene expression that may contribute to NDDs,” the researchers explained. Studies of human embryonic stem cells exposed to acetaminophen during neuronal differentiation have shown alterations in transcriptional and epigenetic regulation during early brain development.
Despite the concerning findings, the researchers emphasised that pregnant women should not stop taking medication without consulting healthcare providers. Untreated pain and fever during pregnancy can also pose serious risks to both mother and child, including neural tube defects and preterm birth.
“While this association warrants caution, untreated maternal fever and pain pose risks such as neural tube defects and preterm birth, necessitating a balanced approach,” the study authors wrote. They recommend “judicious acetaminophen use – lowest effective dose, shortest duration – under medical guidance, tailored to individual risk-benefit assessments, rather than a broad limitation.”
The researchers particularly stressed that high fever during pregnancy can harm foetal development, making fever reduction sometimes necessary. However, they suggested exploring non-pharmacological options for pain and fever management when possible, such as physical cooling methods, and consulting healthcare providers about the safest approach for individual circumstances.
The findings have significant implications for clinical practice and public health policy. The researchers called for updated clinical guidelines that better balance the benefits and risks of acetaminophen use during pregnancy, moving away from the current approach that considers it universally safe.
“The majority of studies show consistency between their results across different time periods, datasets, and patient populations: when a mother takes acetaminophen while pregnant, the odds of her child having an NDD, including ADHD or ASD, increased,” the researchers concluded from their comprehensive analysis.
The study also highlights the urgent need for pharmaceutical innovation to develop safer alternatives for pain and fever management in pregnant women. With limited pharmacological options available – NSAIDs carry teratogenic risks, particularly in the third trimester – there is a clear gap in safe treatment choices for expectant mothers.
It is important to note that these findings do not mean every child exposed to acetaminophen will develop autism or ADHD. Rather, they indicate a statistical increase in risk compared to children whose mothers avoided the drug during pregnancy.
The researchers emphasised that many factors contribute to neurodevelopmental disorders, and acetaminophen exposure is only one potential risk factor among many.
The research team acknowledged that “observational limitations preclude definitive causation,” but argued that the consistency of results across multiple high-quality studies, combined with biological plausibility from experimental research, warrants a precautionary approach.
(Edited by Dese Gowda)
