Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder

doi:10.3390/brainsci8070127

. 2018 Jul 3;8(7):127.

doi: 10.3390/brainsci8070127.

Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder

Yuelong Ji¹, Anne W Riley², Li-Ching Lee^{3

4}, Xiumei Hong⁵, Guoying Wang⁶, Hui-Ju Tsai⁷, Noel T Mueller⁸, Colleen Pearson⁹, Jessica Thermitus¹⁰, Anita Panjwani¹¹, Hongkai Ji¹², Tami R Bartell¹³, Irina Burd¹⁴, M Daniele Fallin^{15

16}, Xiaobin Wang^{17

18}

Affiliations

¹ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. yji7@jhu.edu.
² Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. ariley1@jhu.edu.
³ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. llee38@jhu.edu.
⁴ Wendy Klag Center for Autism and Developmental Disabilities & Department of Mental Health, 615 N Wolfe St, Baltimore, MD 21205, USA. llee38@jhu.edu.
⁵ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. xhong3@jhu.edu.
⁶ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. gwang24@jhu.edu.
⁷ Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan 35053, Taiwan. tsaihj@nhri.org.tw.
⁸ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. noeltmueller@jhu.edu.
⁹ Department of Pediatrics, Boston University School of Medicine and Boston Medical Center, 1 Boston Medical Center Pl, Boston, MA 02118, USA. Colleen.Pearson@bmc.org.
¹⁰ Department of Pediatrics, Boston University School of Medicine and Boston Medical Center, 1 Boston Medical Center Pl, Boston, MA 02118, USA. Jessica.Thermitus@bmc.org.
¹¹ Department of International Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. apanjwani@jhu.edu.
¹² Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. hji@jhu.edu.
¹³ Stanley Manne Children's Research Institute, Mary Ann & J. Milburn Smith Child Health Research, Outreach and Advocacy Center, Ann & Robert H. Lurie Children's Hospital of Chicago, 2430 N Halsted St, Chicago, IL 60614, USA. TBartell@luriechildrens.org.
¹⁴ Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore, MD 21287, USA. iburd@jhmi.edu.
¹⁵ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. dfallin@jhu.edu.
¹⁶ Wendy Klag Center for Autism and Developmental Disabilities & Department of Mental Health, 615 N Wolfe St, Baltimore, MD 21205, USA. dfallin@jhu.edu.
¹⁷ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. xwang82@jhu.edu.
¹⁸ Division of General Pediatrics & Adolescent Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore, MD 21287, USA. xwang82@jhu.edu.

PMID: 29970852
PMCID: PMC6071105
DOI: 10.3390/brainsci8070127

Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder

Yuelong Ji et al. Brain Sci. 2018.

. 2018 Jul 3;8(7):127.

doi: 10.3390/brainsci8070127.

Authors

Affiliations

¹ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. yji7@jhu.edu.
² Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. ariley1@jhu.edu.
³ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. llee38@jhu.edu.
⁴ Wendy Klag Center for Autism and Developmental Disabilities & Department of Mental Health, 615 N Wolfe St, Baltimore, MD 21205, USA. llee38@jhu.edu.
⁵ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. xhong3@jhu.edu.
⁶ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. gwang24@jhu.edu.
⁷ Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan 35053, Taiwan. tsaihj@nhri.org.tw.
⁸ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. noeltmueller@jhu.edu.
⁹ Department of Pediatrics, Boston University School of Medicine and Boston Medical Center, 1 Boston Medical Center Pl, Boston, MA 02118, USA. Colleen.Pearson@bmc.org.
¹⁰ Department of Pediatrics, Boston University School of Medicine and Boston Medical Center, 1 Boston Medical Center Pl, Boston, MA 02118, USA. Jessica.Thermitus@bmc.org.
¹¹ Department of International Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. apanjwani@jhu.edu.
¹² Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. hji@jhu.edu.
¹³ Stanley Manne Children's Research Institute, Mary Ann & J. Milburn Smith Child Health Research, Outreach and Advocacy Center, Ann & Robert H. Lurie Children's Hospital of Chicago, 2430 N Halsted St, Chicago, IL 60614, USA. TBartell@luriechildrens.org.
¹⁴ Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore, MD 21287, USA. iburd@jhmi.edu.
¹⁵ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. dfallin@jhu.edu.
¹⁶ Wendy Klag Center for Autism and Developmental Disabilities & Department of Mental Health, 615 N Wolfe St, Baltimore, MD 21205, USA. dfallin@jhu.edu.
¹⁷ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA. xwang82@jhu.edu.
¹⁸ Division of General Pediatrics & Adolescent Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, 1800 Orleans St, Baltimore, MD 21287, USA. xwang82@jhu.edu.

PMID: 29970852
PMCID: PMC6071105
DOI: 10.3390/brainsci8070127

Abstract

Previous studies have suggested a positive association between self-reported maternal acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in offspring. We sought to examine the prospective association between maternal plasma biomarkers of acetaminophen intake and ADHD diagnosis in the offspring. This report analyzed 1180 children enrolled at birth and followed prospectively as part of the Boston Birth Cohort, including 188 with ADHD diagnosis based on electronic medical record review. Maternal biomarkers of acetaminophen intake were measured in plasma samples obtained within 1⁻3 days postpartum. Odds ratios for having ADHD diagnosis or other developmental disorders were estimated using multinomial logistic regression models, adjusting for pertinent covariables. Compared to neurotypical children, we observed significant positive dose-responsive associations with ADHD diagnosis for each maternal acetaminophen biomarker. These dose⁻responsive associations persisted after adjusting for indication of acetaminophen use and other pertinent covariates; and were specific to ADHD, rather than other neurodevelopmental disorders. In the stratified analyses, differential point estimates of the associations were observed across some strata of covariates. However, these differences were not statistically significant. Maternal acetaminophen biomarkers were specifically associated with increased risk of ADHD diagnosis in offspring. Additional clinical and mechanistic investigations are warranted.

Keywords: ADHD; acetaminophen; pregnancy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Pathways of acetaminophen metabolism (Bolded metabolites were measured in this study).

**Figure 2**
Comparison of the distributions of acetaminophen metabolites and acetaminophen burden by specific diagnosis groups. NT was defined as free of any developmental disorder diagnosis; ADHD was defined as any ADHD diagnosis; ASD only was defined as any ASD diagnosis without having an ADHD diagnosis; other DD was defined as any developmental disorder diagnosis other than ASD and ADHD.

**Figure 3**
The forest plot for the crude association between maternal binary acetaminophen burden and the risk of ADHD diagnosis in offspring across each stratum of pertinent covariables. Acetaminophen burden is the sum of all the acetaminophen metabolites. No detection group is the reference group.

See this image and copyright information in PMC

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References

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[1] Pastor P.N., Duran C., Reuben C. Quickstats: Percentage of children and adolescents aged 5-17 years with diagnosed attention-deficit/hyperactivity disorder (adhd), by race and hispanic ethnicity—National health interview survey, United States, 1997–2014. Morb. Mortal. Wkly. Rep. 2015;64:925.

[2] Pastor P.N., Duran C., Reuben C. Quickstats: Percentage of children and adolescents aged 5-17 years with diagnosed attention-deficit/hyperactivity disorder (adhd), by race and hispanic ethnicity—National health interview survey, United States, 1997–2014. Morb. Mortal. Wkly. Rep. 2015;64:925.

[3] Danielson M.L., Bitsko R.H., Ghandour R.M., Holbrook J.R., Kogan M.D., Blumberg S.J. Prevalence of parent-reported adhd diagnosis and associated treatment among U.S. Children and adolescents, 2016. J. Clin. Child Adolesc. Psychol. 2018;47:199–212. doi: 10.1080/15374416.2017.1417860. - DOI - PMC - PubMed

[4] Danielson M.L., Bitsko R.H., Ghandour R.M., Holbrook J.R., Kogan M.D., Blumberg S.J. Prevalence of parent-reported adhd diagnosis and associated treatment among U.S. Children and adolescents, 2016. J. Clin. Child Adolesc. Psychol. 2018;47:199–212. doi: 10.1080/15374416.2017.1417860. - DOI - PMC - PubMed

[5] Patterson G.R., DeGarmo D., Forgatch M.S. Systematic changes in families following prevention trials. J. Abnorm. Child Psychol. 2004;32:621–633. doi: 10.1023/B:JACP.0000047211.11826.54. - DOI - PubMed

[6] Patterson G.R., DeGarmo D., Forgatch M.S. Systematic changes in families following prevention trials. J. Abnorm. Child Psychol. 2004;32:621–633. doi: 10.1023/B:JACP.0000047211.11826.54. - DOI - PubMed

[7] Scott S., O’Connor T.G., Futh A., Matias C., Price J., Doolan M. Impact of a parenting program in a high-risk, multi-ethnic community: The pals trial. J. Child Psychol. Psychiatry. 2010;51:1331–1341. doi: 10.1111/j.1469-7610.2010.02302.x. - DOI - PubMed

[8] Scott S., O’Connor T.G., Futh A., Matias C., Price J., Doolan M. Impact of a parenting program in a high-risk, multi-ethnic community: The pals trial. J. Child Psychol. Psychiatry. 2010;51:1331–1341. doi: 10.1111/j.1469-7610.2010.02302.x. - DOI - PubMed

[9] Jaffee S.R., Caspi A., Moffitt T.E., Polo-Tomas M., Price T.S., Taylor A. The limits of child effects: Evidence for genetically mediated child effects on corporal punishment but not on physical maltreatment. Dev. Psychol. 2004;40:1047–1058. doi: 10.1037/0012-1649.40.6.1047. - DOI - PubMed

[10] Jaffee S.R., Caspi A., Moffitt T.E., Polo-Tomas M., Price T.S., Taylor A. The limits of child effects: Evidence for genetically mediated child effects on corporal punishment but not on physical maltreatment. Dev. Psychol. 2004;40:1047–1058. doi: 10.1037/0012-1649.40.6.1047. - DOI - PubMed

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Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder

Affiliations

Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder

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Abstract

Conflict of interest statement

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