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Werler  MM, Mitchell  AA, Hernandez-Diaz  S, Honein  MA.  Use of over-the-counter medications during pregnancy.  Am J Obstet Gynecol. 2005;193(3, pt 1):771-777.PubMedGoogle ScholarCrossref
Headley  J, Northstone  K, Simmons  H, Golding  J; ALSPAC Study Team.  Medication use during pregnancy: data from the Avon Longitudinal Study of Parents and Children.  Eur J Clin Pharmacol. 2004;60(5):355-361.PubMedGoogle ScholarCrossref
Rebordosa  C, Kogevinas  M, Bech  BH, Sørensen  HT, Olsen  J.  Use of acetaminophen during pregnancy and risk of adverse pregnancy outcomes.  Int J Epidemiol. 2009;38(3):706-714.PubMedGoogle ScholarCrossref
Jensen  MS, Rebordosa  C, Thulstrup  AM,  et al.  Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism.  Epidemiology. 2010;21(6):779-785.PubMedGoogle ScholarCrossref
Kristensen  DM, Lesné  L, Le Fol  V,  et al.  Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti-androgenic in the rat foetal testis.  Int J Androl. 2012;35(3):377-384.PubMedGoogle ScholarCrossref
Albert  O, Desdoits-Lethimonier  C, Lesné  L,  et al.  Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro.  Hum Reprod. 2013;28(7):1890-1898.PubMedGoogle ScholarCrossref
Colborn  T.  Neurodevelopment and endocrine disruption.  Environ Health Perspect. 2004;112(9):944-949.PubMedGoogle ScholarCrossref
Frye  CA, Bo  E, Calamandrei  G,  et al.  Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems.  J Neuroendocrinol. 2012;24(1):144-159.PubMedGoogle ScholarCrossref
Howdeshell  KL.  A model of the development of the brain as a construct of the thyroid system.  Environ Health Perspect. 2002;110(suppl 3):337-348.PubMedGoogle ScholarCrossref
Rubinow  DR, Schmidt  PJ.  Androgens, brain, and behavior.  Am J Psychiatry. 1996;153(8):974-984.PubMedGoogle Scholar
Polanczyk  G, de Lima  MS, Horta  BL, Biederman  J, Rohde  LA.  The worldwide prevalence of ADHD: a systematic review and metaregression analysis.  Am J Psychiatry. 2007;164(6):942-948.PubMedGoogle ScholarCrossref
Faraone  SV, Sergeant  J, Gillberg  C, Biederman  J.  The worldwide prevalence of ADHD: is it an American condition?  World Psychiatry. 2003;2(2):104-113.PubMedGoogle Scholar
Lee  SI, Schachar  RJ, Chen  SX,  et al.  Predictive validity of DSM-IV and ICD-10 criteria for ADHD and hyperkinetic disorder.  J Child Psychol Psychiatry. 2008;49(1):70-78.PubMedGoogle ScholarCrossref
Millichap  JG.  Etiologic classification of attention-deficit/hyperactivity disorder.  Pediatrics. 2008;121(2):e358-e365.PubMedGoogle ScholarCrossref
Halmøy  A, Klungsøyr  K, Skjærven  R, Haavik  J.  Pre- and perinatal risk factors in adults with attention-deficit/hyperactivity disorder.  Biol Psychiatry. 2012;71(5):474-481.PubMedGoogle ScholarCrossref
Pastor  PN, Reuben  CA.  Diagnosed attention deficit hyperactivity disorder and learning disability: United States, 2004-2006.  Vital Health Stat 10. 2008;(237):1-14.PubMedGoogle Scholar
Møller  LR, Sørensen  MJ, Thomsen  PH.  ICD-10 classification in Danish child and adolescent psychiatry: have diagnoses changed after the introduction of ICD-10 Nord J Psychiatry. 2007;61(1):71-78.PubMedGoogle ScholarCrossref
Marsh  R, Gerber  AJ, Peterson  BS.  Neuroimaging studies of normal brain development and their relevance for understanding childhood neuropsychiatric disorders.  J Am Acad Child Adolesc Psychiatry. 2008;47(11):1233-1251.PubMedGoogle ScholarCrossref
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.PubMedGoogle ScholarCrossref
Olsen  J, Melbye  M, Olsen  SF,  et al.  The Danish National Birth Cohort: its background, structure and aim.  Scand J Public Health. 2001;29(4):300-307.PubMedGoogle ScholarCrossref
Goodman  R.  The Strengths and Difficulties Questionnaire: a research note.  J Child Psychol Psychiatry. 1997;38(5):581-586.PubMedGoogle ScholarCrossref
Andersen  TF, Madsen  M, Jørgensen  J, Mellemkjoer  L, Olsen  JH.  The Danish National Hospital Register: a valuable source of data for modern health sciences.  Dan Med Bull. 1999;46(3):263-268.PubMedGoogle Scholar
Munk-Jørgensen  P, Kastrup  M, Mortensen  PB.  The Danish psychiatric register as a tool in epidemiology.  Acta Psychiatr Scand Suppl. 1993;370:27-32.PubMedGoogle ScholarCrossref
Gaist  D, Sørensen  HT, Hallas  J.  The Danish prescription registries.  Dan Med Bull. 1997;44(4):445-448.PubMedGoogle Scholar
Robbins  AS, Chao  SY, Fonseca  VP.  What’s the relative risk? a method to directly estimate risk ratios in cohort studies of common outcomes.  Ann Epidemiol. 2002;12(7):452-454.PubMedGoogle ScholarCrossref
Bilenberg  N, Hougaard  D, Norgaard-Pedersen  B, Nordenbæk  CM, Olsen  J.  Twin study on transplacental-acquired antibodies and attention deficit/hyperactivity disorder: a pilot study.  J Neuroimmunol. 2011;236(1-2):72-75.PubMedGoogle ScholarCrossref
Mann  JR, McDermott  S.  Are maternal genitourinary infection and pre-eclampsia associated with ADHD in school-aged children?  J Atten Disord. 2011;15(8):667-673.PubMedGoogle ScholarCrossref
Yuan  YC.  Multiple Imputation for Missing Data: Concepts and New Development. Rockville, MD: SAS Institute Inc;2001.
Mazaud-Guittot  S, Nicolaz  CN, Desdoits-Lethimonier  C,  et al.  Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.  J Clin Endocrinol Metab. 2013;98(11):E1757-E1767.PubMedGoogle ScholarCrossref
Ghassabian  A, Bongers-Schokking  JJ, Henrichs  J,  et al.  Maternal thyroid function during pregnancy and behavioral problems in the offspring: the Generation R Study.  Pediatr Res. 2011;69(5, pt 1):454-459.PubMedGoogle ScholarCrossref
Posadas  I, Santos  P, Blanco  A, Muñoz-Fernández  M, Ceña  V.  Acetaminophen induces apoptosis in rat cortical neurons.  PLoS One. 2010;5(12):e15360.PubMedGoogle ScholarCrossref
Ghanizadeh  A.  Acetaminophen may mediate oxidative stress and neurotoxicity in autism.  Med Hypotheses. 2012;78(2):351. PubMedGoogle ScholarCrossref
Kelly  Y, Sacker  A, Gray  R, Kelly  J, Wolke  D, Quigley  MA.  Light drinking in pregnancy, a risk for behavioural problems and cognitive deficits at 3 years of age?  Int J Epidemiol. 2009;38(1):129-140.PubMedGoogle ScholarCrossref
Obel  C, Linnet  KM, Henriksen  TB,  et al.  Smoking during pregnancy and hyperactivity-inattention in the offspring: comparing results from three Nordic cohorts.  Int J Epidemiol. 2009;38(3):698-705.PubMedGoogle ScholarCrossref
Elberling  H, Linneberg  A, Olsen  EM, Goodman  R, Skovgaard  AM.  The prevalence of SDQ-measured mental health problems at age 5-7 years and identification of predictors from birth to preschool age in a Danish birth cohort: the Copenhagen Child Cohort 2000.  Eur Child Adolesc Psychiatry. 2010;19(9):725-735.PubMedGoogle ScholarCrossref
Fei  CY, Olsen  J.  Prenatal exposure to perfluorinated chemicals and behavioral or coordination problems at age 7 years.  Environ Health Perspect. 2011;119(4):573-578.PubMedGoogle ScholarCrossref
Li  J, Olsen  J, Vestergaard  M, Obel  C.  Attention-deficit/hyperactivity disorder in the offspring following prenatal maternal bereavement: a nationwide follow-up study in Denmark.  Eur Child Adolesc Psychiatry. 2010;19(10):747-753.PubMedGoogle ScholarCrossref
Tagaya  H.  Methylphenidate: pharmacology, indication and potential of abuse [in Japanese].  Nihon Rinsho. 2010;68(8):1550-1555.PubMedGoogle Scholar
Olesen  C, Søndergaard  C, Thrane  N, Nielsen  GL, de Jong-van den Berg  L, Olsen  J; EuroMAP Group.  Do pregnant women report use of dispensed medications?  Epidemiology. 2001;12(5):497-501.PubMedGoogle ScholarCrossref
Nohr  EA, Frydenberg  M, Henriksen  TB, Olsen  J.  Does low participation in cohort studies induce bias?  Epidemiology. 2006;17(4):413-418.PubMedGoogle ScholarCrossref
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    1 Comment for this article
    Comparison of the characteristics of women with or without acetaminophen use in pregnancy
    Yona Amitai MD, MPH | Bar Ilan University, Ramat Gan, Israel
    March 4, 2014EditorJAMA PediatricsRe: Comment on the manuscript: Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders, by Liew et alDear Editor, The recent report on association between acetaminophen use in pregnancy with ADHD in childhood1, may bear practical implications for antipyretic use in pregnancy. Since hyperpyrexia in pregnancy has potential adverse effects including congenital malformations, the role of antipyretic medication in pregnancy is crucial. Numerous studies have shown associations between maternal hyperthermia and increased risk for neural tube defects in offspring2,3. Other have found associations between maternal fever and congenital heart defects (CHDs)4,5. Significant associations were found between fever and influenza and specific CHDs, including atrioventricular septal defects in infants with Down syndrome. Maternal antipyretic use in the setting of fever or influenza tended to decrease these associations5. In Liew's report, acetaminophen has been used by 56% of their study population1. The use of ibuprofen and aspirin in this cohort has been reported by others to be 10 fold and 7 fold lower respectively, compared with acetaminophen6. Since smoking, psychiatric illness, fever, infection and other risk factors may be significant risk factors for adverse pregnancy outcome, including ADHD, the detailed report of their occurrence in such a study is important. The report of these characteristics in Table 1 in this study is misleading. The authors compare the frequency of these variables between mothers who have used acetaminophen in pregnancy, with that of the whole group, rather than a direct comparison between those who used or did not use acetaminophen. Such comparison markedly attenuates the differences, since women who used acetaminophen were over half of the whole study population, and they were found to have higher frequency in most of the potential risk factors. Calculation of the frequency of some of these characteristics, based on the reported numbers of patients in their report, illustrate the marked differences between the 2 modes of comparison (Table). For example, the difference in the frequency of fever rose from 28.7% in the whole group and 33.4% in acetaminophen users to 22.7% and 33.4%, respectively (47% higher). Some of these differences are probably statistically (and clinically) significant. Although the differences in ADHD variables remained significant after adjusting for these confounders, the direct comparison of these confounders between acetaminophen users and non-users should be reported, with the p values of the differences. Table 1 Revised with direct comparison between mothers with or without APAP use in pregnancy in the Danish Birth Cohort (selected variables, calculated) Word count: 498 (including table)Yona Amitai, MD, MPHDepartment of Management, Public Health and Health management systemsBar Ilan University52900 Ramat Gan IsraelConflict of Interest: Prof. Amitai is a paid consultant for Teva Pharmaceuticals Ltd, Israel, producer of acetaminophen formulations.Comment:I have prepared a Table, but if I add it as a word file the figures are messed up, please allow me to submit the Table as PDF or in another wayYona AmitaiReferences:1. Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders. JAMA Pediatr. 2014 Feb 24.2. Suarez L1, Felkner M, Hendricks K. The effect of fever, febrile illnesses, and heat exposures on the risk of neural tube defects in a Texas-Mexico border population. Birth Defects Res A Clin Mol Teratol. 2004; 70: 815-9.3. Moretti ME1, Bar-Oz B, Fried S, Koren G. Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis. Epidemiology. 2005; 16: 216-9.4. Botto LD1, Lynberg MC, Erickson JD. Congenital heart defects, maternal febrile illness, and multivitamin use: a population-based study. Epidemiology. 2001; 12:485-90.5. Oster ME1, Riehle-Colarusso T, Alverson CJ, Correa A. Associations between maternal fever and influenza and congenital heart defects. J Pediatr. 2011; 158: 990-5. 6. Jensen MS, Rebordosa C, Thulstrup AM, Toft G, Sørensen HT, Bonde JP, Henriksen TB, Olsen J. Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology. 2010; 21: 779-85
    CONFLICT OF INTEREST: Prof. Yona Amitai is a payed consultant for Teva Pharmaceuticals Industry Ltd. Israel, producer os acetaminophen formulations
    Original Investigation
    April 2014

    Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders

    Author Affiliations
    • 1Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles
    • 2Department of Neurology, School of Medicine, University of California, Los Angeles
    • 3Arizona Respiratory Center, the BIO5 Institute, University of Arizona, Tucson
    • 4Global Clinical Epidemiology, Drug Safety, and Epidemiology, Novartis Farmaceutica SA, Barcelona, Spain
    • 5Department of Health Care Management, College of Healthcare Administration and Management, National Taipei University of Nursing Health Sciences, Taipei, Taiwan
    • 6The Institute of Public Health, University of Aarhus, Aarhus, Denmark
    JAMA Pediatr. 2014;168(4):313-320. doi:10.1001/jamapediatrics.2013.4914

    Importance  Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development.

    Objective  To evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)–like behavioral problems or hyperkinetic disorders (HKDs) in children.

    Design, Setting, and Participants  We studied 64 322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002.

    Exposures  Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth.

    Main Outcomes and Measures  To ascertain outcome information we used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. We estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen.

    Results  More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < .001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mother’s mental health problems, or other potential confounders we evaluated.

    Conclusions and Relevance  Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed.