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. 2020 Feb 1;77(2):180-189.
doi: 10.1001/jamapsychiatry.2019.3259.

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

Yuelong Ji  1 , Romuladus E Azuine  2 , Yan Zhang  3 , Wenpin Hou  4 , Xiumei Hong  1 , Guoying Wang  1 , Anne Riley  1 , Colleen Pearson  5 , Barry Zuckerman  5 , Xiaobin Wang  1   6
Affiliations

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

Yuelong Ji et al. JAMA Psychiatry. .

Abstract

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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Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.
Figure 1.. Distribution of Cord Plasma Acetaminophen Metabolites
Distribution of cord plasma acetaminophen metabolites by the following child physician-diagnosed conditions: neurotypical development (ND), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), ADHD and ASD, and other developmental disabilities (DDs).
Figure 2.
Figure 2.. Forest Plots Summarizing the Subgroup Analyses
Subgroup analyses of the association between cord acetaminophen burden (second and third tertiles vs first tertile) and the risk of attention-deficit/hyperactivity disorder (ADHD) only (A) and the risk of autism spectrum disorder (ASD) only (B) in childhood. Squares represent mean values, with whiskers indicating 95% CIs. NA indicates not applicable.
See this image and copyright information in PMC

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