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Original Investigation
October 30, 2019

Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood

Author Affiliations
  • 1Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
  • 2Division of Research, Office of Epidemiology and Research, Maternal and Child Health Bureau, Health Resources and Services Administration, US Department of Health and Human Services, Rockville, Maryland
  • 3Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
  • 4Department of Computer Science, Johns Hopkins University Whiting School of Engineering, Baltimore, Maryland
  • 5Department of Pediatrics, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts
  • 6Division of General Pediatrics & Adolescent Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
JAMA Psychiatry. Published online October 30, 2019. doi:https://doi.org/10.1001/jamapsychiatry.2019.3259
Key Points

Question  What is the association between cord plasma biomarkers of in utero acetaminophen exposure and risk of childhood attention-deficit/hyperactivity disorder and autism spectrum disorder?

Findings  In this cohort study of 996 mother-infant dyads from the Boston Birth Cohort, cord plasma biomarkers of fetal exposure to acetaminophen were associated with significantly increased risk of childhood attention-deficit/hyperactivity disorder and autism spectrum disorder.

Meaning  These findings suggest in utero exposure to acetaminophen is associated with increased risk of attention-deficit/hyperactivity disorder and autism spectrum disorder in children and warrant additional investigations.


Importance  Prior studies have raised concern about maternal acetaminophen use during pregnancy and increased risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in their children; however, most studies have relied on maternal self-report.

Objective  To examine the prospective associations between cord plasma acetaminophen metabolites and physician-diagnosed ADHD, ASD, both ADHD and ASD, and developmental disabilities (DDs) in childhood.

Design, Setting, and Participants  This prospective cohort study analyzed 996 mother-infant dyads, a subset of the Boston Birth Cohort, who were enrolled at birth and followed up prospectively at the Boston Medical Center from October 1, 1998, to June 30, 2018.

Exposures  Three cord acetaminophen metabolites (unchanged acetaminophen, acetaminophen glucuronide, and 3-[N-acetyl-l-cystein-S-yl]-acetaminophen) were measured in archived cord plasma samples collected at birth.

Main Outcomes and Measures  Physician-diagnosed ADHD, ASD, and other DDs as documented in the child’s medical records.

Results  Of 996 participants (mean [SD] age, 9.8 [3.9] years; 548 [55.0%] male), the final sample included 257 children (25.8%) with ADHD only, 66 (6.6%) with ASD only, 42 (4.2%) with both ADHD and ASD, 304 (30.5%) with other DDs, and 327 (32.8%) who were neurotypical. Unchanged acetaminophen levels were detectable in all cord plasma samples. Compared with being in the first tertile, being in the second and third tertiles of cord acetaminophen burden was associated with higher odds of ADHD diagnosis (odds ratio [OR] for second tertile, 2.26; 95% CI, 1.40-3.69; OR for third tertile, 2.86; 95% CI, 1.77-4.67) and ASD diagnosis (OR for second tertile, 2.14; 95% CI, 0.93-5.13; OR for third tertile, 3.62; 95% CI, 1.62-8.60). Sensitivity analyses and subgroup analyses found consistent associations between acetaminophen buden and ADHD and acetaminophen burden and ASD across strata of potential confounders, including maternal indication, substance use, preterm birth, and child age and sex, for which point estimates for the ORs vary from 2.3 to 3.5 for ADHD and 1.6 to 4.1 for ASD.

Conclusions and Relevance  Cord biomarkers of fetal exposure to acetaminophen were associated with significantly increased risk of childhood ADHD and ASD in a dose-response fashion. Our findings support previous studies regarding the association between prenatal and perinatal acetaminophen exposure and childhood neurodevelopmental risk and warrant additional investigations.

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    2 Comments for this article
    Cross comparison
    devrim ulusal, Md | Researcher
    Congrats .great article and good study.
    Did you analyze the cause of acetaminophen usage with the primary end points. If so, is there any link between them besides the drug usage?

    Thanks in advance

    Best Regards

    Dr. Devrim Ulusal
    Epidemiology Of Acetaminophen exposure and Autism
    James Little, MD | Jackson Pediatrics
    I'm just an old general pediatrician who has watched this subject for some time.

    It has seem to me, for a long time, that the marked increase in the frequency of Autism Spectrum Disorders (and ADHD) could more readily be associated with the timing of the change from use of ASA to Acetaminophen with the recognition of the association of Reyes Syndrome with ASA use and the rapid discontinuation of ASA use that followed.

    I think that the hysteria over immunizations and the association of ASD with Measles Vaccine promulgated by Wakefield, and the years of studies undertaken
    to disprove that fable, diverted attention away from a serious look at the safety and epidemiology associated with the rapid and abundant substitution of Acetaminophen for ASA.

    Maybe the time has come to look more closely at the "perceived safety" of Acetaminophen.

    James Little Sr MD FAAP
    Jackson Pediatrics
    Jackson, WY