Prenatal Acetaminophen Exposure and its Associated Risk for Attention Deficit Hyperactivity Disorder
Acetaminophen is one of the most commonly used over-the-counter antipyretic and analgesic drugs on the market and has been relevant in the medical world for almost a hundred years. It has maintained an excellent reputation as a safe therapeutic in several types of patient profiles. However, the number of children diagnosed with neurodevelopmental disorders, namely ADHD, have been on the rise. Recent findings have indicated an association between in utero exposure to acetaminophen and an increased risk of developing neurodevelopmental disorders such as ADHD in offspring. The mechanism by which this potential side effect occurs is difficult to pinpoint. However, it is known that the metabolism of acetaminophen is known to cause oxidative stress, which has been shown to influence the developing fetus. This review highlights the epidemiological data indicating the correlation between prenatal acetaminophen exposure and ADHD and discusses several proposed theories by which this phenomenon may occur. While there is not yet enough clinical evidence to prove that acetaminophen may cause ADHD, there is a strong enough correlation to indicate a warning to pregnant patients of the potential risks. The risks and benefits of treatment should be considered so that the patient may continue with the course of action with the most favorable outcome. This review was mainly based on manuscripts pulled from Google Scholar and PubMed. The purpose of this literature review is to assist clinicians to better understand lesser-known risks in acetaminophen usage in pregnant patients.
1. Józwiak-Bebenista M, Nowak JZ. Paracetamol: mechanism of action, applications and safety concern. Acta Pol Pharm. 2014;71(1):11-23.
2. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent Patterns of Medication Use in the Ambulatory Adult Population of the United StatesThe Slone Survey. JAMA. 2002;287(3):337-344. doi:10.1001/jama.287.3.337
3. Servey J, Chang J. Over-the-Counter Medications in Pregnancy. Am Fam Physician. 2014;90(8):548-555.
4. Patel E, Jones JP III, Bono-Lunn D, et al. The safety of pediatric use of paracetamol (acetaminophen): a narrative review of direct and indirect evidence. Minerva Pediatr. 2022;74(6):774-788. doi:10.23736/S2724-5276.22.06932-4
5. Teleanu DM, Niculescu AG, Lungu II, et al. An Overview of Oxidative Stress, Neuroinflammation, and Neurodegenerative Diseases. Int J Mol Sci. 2022;23(11):5938. doi:10.3390/ijms23115938
6. Data and Statistics About ADHD| CDC. Centers for Disease Control and Prevention. June 8, 2022. Accessed May 16, 2023. https://www.cdc.gov/ncbddd/adhd/data.html
7. Bauer AZ, Swan SH, Kriebel D, et al. Paracetamol use during pregnancy- a call for precautionary action. Nat Rev Endocrinol. 2021;17(12):757-766. doi:10.1038/s41574-021-00553-7
8. Peasgood T, Bhardwaj A, Biggs K, et al. The impact of ADHD on the health and well-being of ADHD children and their siblings. Eur Child Adolesc Psychiatry. 2016;25(11):1217-1231. doi:10.1007/s00787-016-0841-6
9. Franke B, Michelini G, Asherson P, et al. Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan. Eur Neuropsychopharmacol. 2018;28(10):1059-1088. doi:10.1016/j.euroneuro.2018.08.001
10. NIH-funded study suggests acetaminophen exposure in pregnancy linked to higher risk of ADHD, autism. National Institutes of Health (NIH). October 30, 2019. Accessed May 16, 2023. https://www.nih.gov/news-events/news-releases/nih-funded-study-suggests-acetaminophen-exposure-pregnancy-linked-higher-risk-adhd-autism
11. Bührer C, Endesfelder S, Scheuer T, Schmitz T. Paracetamol (Acetaminophen) and the Developing Brain. Int J Mol Sci. 2021;22(20). doi:10.3390/ijms222011156
12. Gou X, Wang Y, Tang Y, et al. Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis. Aust N Z J Psychiatry. 2019;53(3):195-206. doi:10.1177/0004867418823276
13. Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013;42(6):1702-1713. doi:10.1093/ije/dyt183
14. Sznajder KK, Teti DM, Kjerulff KH. Maternal use of acetaminophen during pregnancy and neurobehavioral problems in offspring at 3 years: A prospective cohort study. PLOS ONE. 2022;17(9):e0272593. doi:10.1371/journal.pone.0272593
15. Ji Y, Azuine RE, Zhang Y, et al. Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood. JAMA Psychiatry. 2020;77(2):180-189. doi:10.1001/jamapsychiatry.2019.3259
16. Baker BH, Lugo-Candelas C, Wu H, et al. Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity. JAMA Pediatr. 2020;174(11):1-9. doi:10.1001/jamapediatrics.2020.3080
17. Alemany S, Avella-Garcia C, Liew Z, et al. Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts. Eur J Epidemiol. 2021;36(10):993-1004. doi:10.1007/s10654-021-00754-4
18. Masarwa R, Levine H, Gorelik E, Reif S, Perlman A, Matok I. Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies. Am J Epidemiol. 2018;187(8):1817-1827. doi:10.1093/aje/kwy086
19. Khan FY, Kabiraj G, Ahmed MA, et al. A Systematic Review of the Link Between Autism Spectrum Disorder and Acetaminophen: A Mystery to Resolve. Cureus. 14(7):e26995. doi:10.7759/cureus.26995
20. Ystrom E, Vollrath ME, Nordeng H. Effects of personality on use of medications, alcohol, and cigarettes during pregnancy. Eur J Clin Pharmacol. 2012;68(5):845-851. doi:10.1007/s00228-011-1197-y
21. Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014;168(4):313-320. doi:10.1001/jamapediatrics.2013.4914
22. 204767s000lbl.pdf. Accessed May 16, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204767s000lbl.pdf
23. Mazaleuskaya LL, Sangkuhl K, Thorn CF, FitzGerald GA, Altman RB, Klein TE. PharmGKB summary: Pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015;25(8):416-426. doi:10.1097/FPC.0000000000000150
24. Gerriets V, Anderson J, Nappe TM. Acetaminophen. In: StatPearls. StatPearls Publishing; 2023. Accessed May 16, 2023. http://www.ncbi.nlm.nih.gov/books/NBK482369/
25. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S. Paracetamol: New Vistas of an Old Drug. CNS Drug Rev. 2006;12(3-4):250-275. doi:10.1111/j.1527-3458.2006.00250.x
26. Hogestatt ED, Jonsson BAG, Ermund A, et al. Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem. 2005;280(36):31405-31412. doi:10.1074/jbc.M501489200
27. Attention deficit hyperactivity disorder- The Lancet. Accessed May 16, 2023. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00238-X/fulltext
28. Kian N, Samieefar N, Rezaei N. Prenatal risk factors and genetic causes of ADHD in children. World J Pediatr WJP. 2022;18(5):308-319. doi:10.1007/s12519-022-00524-6
29. Cendejas-Hernandez J, Sarafian JT, Lawton VG, et al. Paracetamol (acetaminophen) use in infants and children was never shown to be safe for neurodevelopment: a systematic review with citation tracking. Eur J Pediatr. 2022;181(5):1835-1857. doi:10.1007/s00431-022-04407-w
30. Angelis D, Chalak L. Acetaminophen and the developing brain: A critical review of the evidence. Early Hum Dev. 2021;159:105411. doi:10.1016/j.earlhumdev.2021.105411
31. Bauer AZ, Kriebel D, Herbert MR, Bornehag CG, Swan SH. Prenatal paracetamol exposure and child neurodevelopment: A review. Horm Behav. 2018;101:125-147. doi:10.1016/j.yhbeh.2018.01.003
32. Gervin K, Nordeng H, Ystrom E, Reichborn-Kjennerud T, Lyle R. Long-term prenatal exposure to paracetamol is associated with DNA methylation differences in children diagnosed with ADHD. Clin Epigenetics. 2017;9(1):77. doi:10.1186/s13148-017-0376-9
33. Anand NS, Raghavan R, Wang G, et al. Perinatal Acetaminophen Exposure and Childhood Attention-Deficit/Hyperactivity Disorder (ADHD): Exploring the Role of Umbilical Cord Plasma Metabolites in Oxidative Stress Pathways. Brain Sci. 2021;11(10):1302. doi:10.3390/brainsci11101302
34. Bremer L, Goletzke J, Wiessner C, et al. Paracetamol Medication During Pregnancy: Insights on Intake Frequencies, Dosages and Effects on Hematopoietic Stem Cell Populations in Cord Blood From a Longitudinal Prospective Pregnancy Cohort. EBioMedicine. 2017;26:146-151. doi:10.1016/j.ebiom.2017.10.023