Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability

Abstract

Importance: 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.

Figure 1.. Flow of Participants in a Study of Acetaminophen Use During Pregnancy and Risk of Neurodevelopmental Disorders

Figure 2.. Prevalence of Analgesic Use During Pregnancy and Neurodevelopmental Disorder Incidence (N = 2 480 797 Children)

Prevalence of analgesic use during pregnancy was 185 909 (7.5%) for acetaminophen, 39 811 (1.6%) for aspirin, 61 597 (2.5%) for nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs), 81 970 (3.3%) for opioid medications, and 19 687 (0.8%) for antimigraine medications. Cumulative incidence of neurodevelopmental disorders was 68 584 (2.8%) for autism, 146 386 (5.9%) for attention-deficit/hyperactivity disorder (ADHD), and 24 554 (1.0%) for intellectual disorder.

Figure 3.. Association Between Analgesic Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability

Absolute risk difference is the difference in absolute risk at 10 years of age between exposed and unexposed children, expressed as a percentage. For example, the 0.09% absolute difference for acetaminophen and autism can be interpreted as follows: the risk of child autism at 10 years of age is 0.09% higher with acetaminophen use compared with no acetaminophen use. The population-based model was adjusted for birth cohort; child sex; all other analgesics; birthing parent’s diagnoses of migraine, chronic pain, infections, fevers, rheumatoid arthritis, and headaches; calendar period of delivery; parity; age at delivery (linear and cubic term); country of birth; residential region; cohabitation at delivery; early pregnancy body mass index; smoking status; diagnosis of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability; history of psychiatric conditions and prescription use of psycholeptics, antidepressants, and antiseizure medication; health care visits in the year before pregnancy and an inadequate number of antenatal visits; and the highest household education and disposable income. The sibling control model was adjusted for all of the above excluding birthing parent’s birth country, psychiatric history, and diagnosis autism, ADHD, and intellectual disability. NSAID indicates nonsteroidal anti-inflammatory drug.