Association Between Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy.
OBJECTIVE
To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability.
DESIGN, SETTING, AND PARTICIPANTS
This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021.
EXPOSURE
Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records.
MAIN OUTCOMES AND MEASURES
Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers.
RESULTS
In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively.
CONCLUSIONS AND RELEVANCE
Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.
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Additional Info
Disclosure statements are available on the authors' profiles:
Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability
JAMA 2024 Apr 09;331(14)1205-1214, VH Ahlqvist, H Sjöqvist, C Dalman, H Karlsson, O Stephansson, S Johansson, C Magnusson, RM Gardner, BK LeeFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Acetaminophen use in pregnancy
Many of us have likely found ourselves in the middle of a prenatal visit feeling limited by the medications we can safely offer our patients. Everyday issues suddenly become challenging to treat when the everyday medications are not considered to be safe in pregnancy. Since we cannot rely on NSAIDs when the issue in question is pain, headache, migraine, or the occasional fever, our answers are often the same: you can try some acetaminophen.
Given the ease and frequency of acetaminophen use, when multiple studies came out showing a potential link between its use in pregnancy and behavioral problems in childhood, many of us who practice prenatal care became concerned. Do we need to add acetaminophen to the long list of medications that should not be taken in pregnancy?
This recently published population-based study out of Sweden proposes that the connection observed in prior studies is more likely explained by confounding. This new study looked at all singleton liveborn children born in Sweden between 1995 and 2019 and included a sample of over 1.3 million pregnant patients and over 2.4 million children.
The researchers used sibling controls to account for any unidentified genetic and environmental confounders. Although the results at the general population level were consistent with those from prior studies and showed a slight association between acetaminophen use and childhood neurodevelopmental disorders (HR, 1.07), this association disappeared entirely for all three categories of neurodevelopmental disorders when compared with a sibling control. Based on these data, unmeasured confounding appears to have been responsible for previously observed associations.
This study contains data on acetaminophen use collected prospectively with obstetric visits as opposed to a retrospective questionnaire, and the number of study participants is impressively large. Although there remains a potential for error in reporting the exposure to acetaminophen, the results of the sibling control are unlikely to be affected by this. Sweden is also a small country with socioeconomic and public health demographics that differ from the US; however, acetaminophen use and neurodevelopmental disorders are widely present across both populations and, as such, this study is adequately generalizable.
A major difficulty in studying a pregnant population is the inability to ethically perform a randomized controlled trial in the vast majority of study scenarios. This may perpetually mean that our data on pregnant patients can feel incomplete. Based on this latest publication, it seems reasonable to continue prenatal acetaminophen use. However, it would also be reasonable — and arguably a requirement — to inform our pregnant patients of this ongoing area of study and participate in shared decision–making. As reassuring as these results are, the informed decision of whether to take acetaminophen during pregnancy should ultimately be left to the patient.