Acetaminophen Use During Pregnancy: Sibling Study Finds No Link to ASD, ADHD

A large, sibling-matched study published in JAMA Pediatrics has yielded inconclusive results regarding a potential link between maternal acetaminophen use during pregnancy and the subsequent development of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children. The research, led by Zeyan Liew, PhD, MPH, of Yale School of Public Health, analyzed data from over 2 million births in Taiwan, seeking to clarify conflicting findings from previous studies. While initial analyses suggested a possible association, this disappeared when researchers focused on siblings, raising questions about the study design and the complexities of disentangling risk factors for neurodevelopmental conditions.

Sibling Rivalry and Study Design

The study leveraged a unique dataset linking health records from Taiwan, encompassing over 2 million singleton births between 2004 and 2015. Crucially, the researchers included over 1.2 million children with at least one sibling, allowing for a “sibling-matched” analysis. This approach aims to control for shared genetic and environmental factors between siblings, potentially isolating the effect of acetaminophen exposure. Approximately 48% of mothers in the cohort received two or more prescriptions for acetaminophen during pregnancy.

The initial, full-cohort analysis revealed a modest association between acetaminophen prescriptions and both ADHD (HR = 1.12; 95% CI, 1.1-1.14) and ASD (HR = 1.06; 95% CI, 1.03-1.09). However, when the analysis was restricted to sibling pairs, these associations vanished, with hazard ratios falling to 0.99 (95% CI, 0.96-1.03) for ADHD and 0.98 (95% CI, 0.9-1.07) for ASD. This null finding in the sibling-matched analysis is the study’s primary takeaway.

“The idea of studying siblings is that any shared underlying risk factors between the siblings will be controlled for in the study design, which is a strength,” explained Liew. “However, we also know that the sibling comparison design is not a randomized study… as with any other health study, replication with methodological inspection is key and necessary.”

Acetaminophen and Neurodevelopment: A Complex Picture

The question of whether acetaminophen use during pregnancy impacts neurodevelopment has been the subject of intense debate in recent years. Several observational studies have suggested a possible link, raising concerns among pregnant individuals and healthcare providers. However, these studies have been plagued by methodological limitations, including the potential for confounding factors and recall bias. An umbrella review published in November 2025 did not find a clear link between acetaminophen and autism or ADHD, adding to the uncertainty.

The current study adds another layer of complexity. The fact that the sibling-matched analysis yielded null results suggests that shared familial factors – genetics, socioeconomic status, parental behaviors – may play a more significant role in the development of ADHD and ASD than previously thought. It also highlights the challenges of isolating the specific effect of acetaminophen exposure.

Divergent Patterns and Methodological Concerns

Interestingly, the researchers also explored a bidirectional analysis, examining outcomes based on which sibling – the older or younger – was exposed to acetaminophen. They found that if only the older sibling was exposed, there was a positive association with both ADHD and ASD. Conversely, if only the younger sibling was exposed, the association was negative. This “divergent pattern” raised concerns about the validity of the sibling-matched design.

“For the sibling design to work and make sense, we do not want these ‘divergent patterns’ to exist,” Liew told Healio. “This gives us pause to conclude whether the sibling design has produced more or less valid findings, compared with the traditional approach studying the full population.”

What Does This Mean for Pregnant Individuals?

Liew emphasized that treatment recommendations should not be altered based on this research. “Generally, researchers still worry that maternal chronic health, genetics and behavioral factors are driving the positive associations between acetaminophen use in pregnancy and childhood neurodevelopment in the population,” he said. “Our study highlights that these are still highly valid questions to ask and need to be carefully studied.”

Acetaminophen remains a commonly recommended pain reliever and fever reducer during pregnancy, as alternatives may carry different risks. Pregnant individuals should continue to follow the guidance of their healthcare providers regarding pain management. The CDC provides information on the safe use of medications during pregnancy, including acetaminophen.

Ongoing Research and Future Directions

The debate surrounding acetaminophen and neurodevelopment is far from settled. Researchers are continuing to investigate the potential risks and benefits of acetaminophen use during pregnancy, employing a variety of study designs and analytical techniques. Future research will likely focus on identifying specific genetic and environmental factors that may interact with acetaminophen exposure to influence neurodevelopmental outcomes. ClinicalTrials.gov lists ongoing studies investigating this topic.

The findings from this study underscore the importance of considering the complexities of study design and the limitations of observational research. While the sibling-matched approach offers a valuable tool for controlling for confounding factors, This proves not without its challenges. Further research, including randomized controlled trials (which are ethically tough to conduct in this context), will be needed to definitively determine the relationship between acetaminophen use during pregnancy and the risk of ADHD and ASD.

Zeyan Liew, PhD, MPH, can be reached at [email protected].