Reference: Paediatr Perinat Epidemiol. 2025 Sep 2 early online
Practice Point: Acetaminophen remains a safe option for treating fever during pregnancy, as the best available evidence suggests it does not pose a neurodevelopmental risk to offspring.
EBM Pearl: Observational studies are prone to bias due to confounding variables, and performing analyses to control for these confounders is crucial for a clear understanding of the relationship between exposures and outcomes.
Recently, concerns have been raised about the safety of acetaminophen (paracetamol outside the United States, and brand name Tylenol) exposure in pregnancy, particularly regarding whether children exposed to the medication in utero have an increased risk of developing neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), or intellectual disability (ID). Acetaminophen use during pregnancy isn’t just common, it’s often the only viable option for managing fever in this population, as other medications carry higher risks. With no safer alternatives currently recommended, understanding its safety profile is critical.
There is a sea of seemingly conflicting evidence on this topic, with some studies claiming an association with neurodevelopmental disorders and others finding no such link. But a new Japanese study was recently published that sharply tips the scales in the direction of no link and helps clear up these concerns. What makes this study stand out? Let’s dive in.
This was a retrospective cohort study that included over 180,000 people who gave birth between 2005 and 2022. The researchers used data from a nationwide insurance database representing about 13% of the total population in Japan. They assessed for acetaminophen use at any time during pregnancy, along with records of medical diagnoses of ASD, ADHD, and ID in offspring.
In the first of two planned analyses, a propensity score-matched multivariable analysis found a slight association between maternal acetaminophen use and the risk of neurodevelopmental disorders (hazard ratio 1.08, 95% CI 1-1.16 for the composite outcome of any neurodevelopmental disorder, with similar values for each of the individual disorders). This result aligns with findings from several earlier studies that performed a similar analysis.
However, neurodevelopmental disorders are highly heritable, and genetics is an important confounding variable that is not captured in the analysis described above. In observational studies, these potentially confounding factors must be carefully controlled for; otherwise, it’s easy to mistake correlation with causation.
To address this issue, the authors performed a sibling-controlled analysis in which they compared sibling pairs wherein one child was exposed to acetaminophen in utero and the other wasn’t. If acetaminophen exposure were a causal factor for neurodevelopmental disorders, one would expect that ASD, ADHD, and ID would be much more common in exposed children compared to their siblings, despite their similar genetic and environmental background. Instead, they found no such association, and the effect found in the previous analysis disappeared: adjusted hazard ratio 0.87, 95% CI 0.69-1.11. The sibling control is what sets this study apart from most previous studies that investigated this issue, which failed to account for genetics and other environmental factors (in addition to numerous other methodologic concerns—the full story there can be found in an upcoming article in our Blog).
This study cleanly replicates a Swedish cohort study from last year. Those authors performed a similar sibling-controlled analysis in a cohort of nearly 2.5 million children and likewise found no association between acetaminophen use in pregnancy and neurodevelopmental disorders in offspring. Taken together, these two large studies point strongly toward a lack of a meaningful association.
So, is this the final answer on the topic? It’s a big step in that direction, but we do need to acknowledge that both of these studies are still only retrospective cohorts based on past medical records. To prove causality, or the lack thereof, we would need a randomized controlled trial, which is unlikely to be possible for ethical reasons. But for now, these findings are very reassuring and are about the highest quality we will get for observational studies. At this point, we don’t have compelling evidence that acetaminophen use during pregnancy poses a neurodevelopmental risk to offspring. Given that maternal fever itself has been clearly demonstrated to be harmful to the mother and the fetus, acetaminophen should not be outright avoided as it remains the safest option we have.
For more information, see the topic Medication and Drug Exposure in Pregnancy in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Claire Symanski, PhD, Medical Editor and Team Lead for ENT at DynaMed. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, MPH, FACP, Senior Deputy Editor at DynaMed; McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Clinical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.