Biomarkers Link Acetaminophen Use to Attention Deficit Hyperactivity Disorder in Offspring

Written by Joyce Smith, BS. Maternal acetaminophen biomarkers were specifically associated with increased risk of ADHD diagnosis in offspring.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that has risen significantly in the U.S. (7.0% to 0.2 %) in the last twenty years ¹.  Genetic mutations do not appear to play a role in ADHD; however, social and environmental risk factors such as maternal obesity ², smoking ³ and drinking ³, low birthweight and preterm birth ⁴, exposure to pesticides such as organophosphates ⁵ and polychlorinated bisphenols ⁶, and lead exposure ⁶ have all been linked to ADHD. Acetaminophen, recommended as an over-the-counter medication for fever and pain relief during pregnancy, is used by over 65% of U.S. and 50% of European pregnant women, and may also be a contributor to ADHD in offspring.  Acetaminophen works by inhibiting prostaglandin synthesis. Prostaglandins are a group of hormone-like substances made at sites of tissue damage or infection and are involved in injury and illness. They not only control processes such as inflammation and reduce fever, but also play important roles in brain function ⁷, learning ⁸ and cerebellar development ⁹.

Wang and associates ¹⁰ sought to clarify whether acetaminophen taken during pregnancy plays a potential adverse role in the developing fetal brain. Their goal was to evaluate any prospective associations between maternal plasma acetaminophen metabolite levels measured within a few days post-delivery and the occurrence of physician-diagnosed ADHD, autism spectrum disorder (ASD), or both, as well as any developmental disabilities in childhood.

They analyzed 1180 children who were enrolled at birth and followed prospectively as part of the Boston Birth Cohort. Of the 1,180 children, 188 were diagnosed with ADHD based on electronic medical record review and also had sufficient cord blood to provide plasma samples for metabolite assays. The plasma samples of cord blood (obtained within 1–3 days postpartum) was measured for two metabolites (maternal biomarkers) of acetaminophen intake: glucuronide and 3-(N-acetyl-L-cysteine-S-yl)-acetaminophen as well as composites of both.

When children were evaluated at a mean age of 10 years, 25.8% were diagnosed with ADHD, 6.6% with ASD, and 4.2% with both. Thirty percent were diagnosed with other development disorders and the remaining one-third were neurotypical. Compared to the neurotypical children, researchers observed significant positive dose-responsive associations with ADHD diagnosis for each maternal acetaminophen biomarker. Of the mother-child pairs, those with the higher levels of acetaminophen exposure (a measure of biomarkers in cord blood post-delivery) had a significantly higher offspring risk of a later ADHD or ASD diagnosis. The odds ratio for infant ADHD diagnosis in the highest tertile of acetaminophen exposure versus the lowest tertile was 2.86 (95%CI 1.77-4.67) while the odds ratio for ASD diagnosis was 3.62 (95% CI 1.62-8.60) for the highest versus lowest tertiles.

Also, compared to mothers of neurotypical children, researchers found that mothers of ADHD or ASD children were more likely to have higher body mass indexes, reported feeling more stressed during pregnancy and reported smoking or drinking before or during pregnancy. In addition, compared to neurotypical children, children with ADHD and ASD were more likely to be male, born prematurely, and with lower birthweights.

Study limitations included data that was not adjusted for family history of ADHD and ASD, or genetic factors related to risk for these conditions, nor was an adjustment made for other medications that may have been used during childbirth such as anticonvulsant drugs or anesthetic agents. Also, acetaminophen exposure was measured only at time of birth; therefore, the full extent and timing of acetaminophen exposure could not be evaluated. The authors did not measure for acetaminophen sulfate, thus the total acetaminophen burden on newborns could not be evaluated. Lastly, there was no placebo group of mothers who were not exposed to acetaminophen. More studies are needed to further clarify these findings. Also, healthcare providers and parents alike may want to consider the benefits and risks of acetaminophen use during pregnancy.

Source: Ji, Yuelong, Anne Riley, Li-Ching Lee, Xiumei Hong, Guoying Wang, Hui-Ju Tsai, Noel Mueller et al. “Maternal biomarkers of acetaminophen use and offspring attention deficit hyperactivity disorder.” Brain sciences 8, no. 7 (2018): 127.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Posted December 9, 2019.

Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from  the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.

References:

1. Pastor P, 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. Morbidity and Mortality Weekly Report. 2015;64(33):925.
2. Rodriguez A, Miettunen J, Henriksen TB, et al. Maternal adiposity prior to pregnancy is associated with ADHD symptoms in offspring: evidence from three prospective pregnancy cohorts. International journal of obesity. 2008;32(3):550.
3. Linnet KM, Dalsgaard S, Obel C, et al. Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: review of the current evidence. American Journal of Psychiatry. 2003;160(6):1028-1040.
4. Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand K. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. Jama. 2002;288(6):728-737.
5. Bouchard MF, Bellinger DC, Wright RO, Weisskopf MG. Attention-deficit/hyperactivity disorder and urinary metabolites of organophosphate pesticides. Pediatrics. 2010;125(6):e1270-e1277.
6. Eubig PA, Aguiar A, Schantz SL. Lead and PCBs as risk factors for attention deficit/hyperactivity disorder. Environmental health perspectives. 2010;118(12):1654-1667.
7. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron. 1993;11(2):371-386.
8. Shaw KN, Commins S, O’mara SM. Deficits in spatial learning and synaptic plasticity induced by the rapid and competitive broad‐spectrum cyclooxygenase inhibitor ibuprofen are reversed by increasing endogenous brain‐derived neurotrophic factor. European Journal of Neuroscience. 2003;17(11):2438-2446.
9. Dean SL, Knutson JF, Krebs‐Kraft DL, McCarthy MM. Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period. European Journal of Neuroscience. 2012;35(8):1218-1229.
10. Ji Y, Riley A, Lee L-C, et al. Maternal biomarkers of acetaminophen use and offspring attention deficit hyperactivity disorder. Brain sciences. 2018;8(7):127.