Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood: Evidence Against Confounding | Child Development | JAMA Pediatrics | JAMA Network
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1.
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
2.
Lupattelli  A, Spigset  O, Twigg  MJ,  et al.  Medication use in pregnancy: a cross-sectional, multinational web-based study.  BMJ Open. 2014;4(2):e004365.PubMedGoogle ScholarCrossref
3.
Viberg  H, Eriksson  P, Gordh  T, Fredriksson  A.  Paracetamol (acetaminophen) administration during neonatal brain development affects cognitive function and alters its analgesic and anxiolytic response in adult male mice.  Toxicol Sci. 2014;138(1):139-147.PubMedGoogle ScholarCrossref
4.
Patel  J, Landers  K, Li  H, Mortimer  RH, Richard  K.  Thyroid hormones and fetal neurological development.  J Endocrinol. 2011;209(1):1-8.PubMedGoogle ScholarCrossref
5.
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
6.
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.PubMedGoogle ScholarCrossref
7.
Thompson  JM, Waldie  KE, Wall  CR, Murphy  R, Mitchell  EA; ABC study group.  Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years.  PLoS One. 2014;9(9):e108210.PubMedGoogle ScholarCrossref
8.
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.PubMedGoogle ScholarCrossref
9.
Plomin  R.  Genotype-environment correlation in the era of DNA.  Behav Genet. 2014;44(6):629-638.PubMedGoogle ScholarCrossref
10.
Thapar  A, Rice  F, Hay  D,  et al.  Prenatal smoking might not cause attention-deficit/hyperactivity disorder: evidence from a novel design.  Biol Psychiatry. 2009;66(8):722-727.PubMedGoogle ScholarCrossref
11.
Rice  F, Harold  GT, Boivin  J, Hay  DF, van den Bree  M, Thapar  A.  Disentangling prenatal and inherited influences in humans with an experimental design.  Proc Natl Acad Sci U S A. 2009;106(7):2464-2467.PubMedGoogle ScholarCrossref
12.
de Fays  L, Van Malderen  K, De Smet  K,  et al.  Use of paracetamol during pregnancy and child neurological development.  Dev Med Child Neurol. 2015;57(8):718-724.PubMedGoogle ScholarCrossref
13.
Shaheen  SO, Newson  RB, Smith  GD, Henderson  AJ.  Prenatal paracetamol exposure and asthma: further evidence against confounding.  Int J Epidemiol. 2010;39(3):790-794.PubMedGoogle ScholarCrossref
14.
Smith  GD.  Assessing intrauterine influences on offspring health outcomes: can epidemiological studies yield robust findings?  Basic Clin Pharmacol Toxicol. 2008;102(2):245-256.PubMedGoogle ScholarCrossref
15.
Leary  SD, Smith  GD, Rogers  IS, Reilly  JJ, Wells  JC, Ness  AR.  Smoking during pregnancy and offspring fat and lean mass in childhood.  Obesity (Silver Spring). 2006;14(12):2284-2293.PubMedGoogle ScholarCrossref
16.
Boyd  A, Golding  J, Macleod  J,  et al.  Cohort Profile: the ‘children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children.  Int J Epidemiol. 2013;42(1):111-127.PubMedGoogle ScholarCrossref
17.
Fraser  A, Macdonald-Wallis  C, Tilling  K,  et al.  Cohort Profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort.  Int J Epidemiol. 2013;42(1):97-110.PubMedGoogle ScholarCrossref
18.
Goodman  R.  The Strengths and Difficulties Questionnaire: a research note.  J Child Psychol Psychiatry. 1997;38(5):581-586.PubMedGoogle ScholarCrossref
19.
Hinds  DA, McMahon  G, Kiefer  AK,  et al.  A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci.  Nat Genet. 2013;45(8):907-911.PubMedGoogle ScholarCrossref
20.
Purcell  SM, Wray  NR, Stone  JL,  et al; International Schizophrenia Consortium.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.  Nature. 2009;460(7256):748-752.PubMedGoogle Scholar
21.
Stergiakouli  E, Hamshere  M, Holmans  P,  et al; deCODE Genetics; Psychiatric GWAS Consortium.  Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD.  Am J Psychiatry. 2012;169(2):186-194.PubMedGoogle ScholarCrossref
22.
Hamshere  ML, Stergiakouli  E, Langley  K,  et al.  Shared polygenic contribution between childhood attention-deficit hyperactivity disorder and adult schizophrenia.  Br J Psychiatry. 2013;203(2):107-111.PubMedGoogle ScholarCrossref
23.
Stergiakouli  E, Martin  J, Hamshere  ML,  et al.  Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) traits in children and clinical ADHD.  J Am Acad Child Adolesc Psychiatry. 2015;54(4):322-327.PubMedGoogle ScholarCrossref
24.
Purcell  S, Neale  B, Todd-Brown  K,  et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses.  Am J Hum Genet. 2007;81(3):559-575.PubMedGoogle ScholarCrossref
25.
Levy  F, Hay  DA, McStephen  M, Wood  C, Waldman  I.  Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study.  J Am Acad Child Adolesc Psychiatry. 1997;36(6):737-744.PubMedGoogle ScholarCrossref
26.
Rollins  DE, von Bahr  C, Glaumann  H, Moldéus  P, Rane  A.  Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells.  Science. 1979;205(4413):1414-1416.PubMedGoogle ScholarCrossref
27.
Nuttall  SL, Khan  JN, Thorpe  GH, Langford  N, Kendall  MJ.  The impact of therapeutic doses of paracetamol on serum total antioxidant capacity.  J Clin Pharm Ther. 2003;28(4):289-294.PubMedGoogle ScholarCrossref
28.
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
29.
Goodman  R, Ford  T, Simmons  H, Gatward  R, Meltzer  H.  Using the Strengths and Difficulties Questionnaire (SDQ) to screen for child psychiatric disorders in a community sample.  Int Rev Psychiatry. 2003;15(1-2):166-172.PubMedGoogle ScholarCrossref
30.
Dudbridge  F.  Power and predictive accuracy of polygenic risk scores.  PLoS Genet. 2013;9(3):e1003348.PubMedGoogle ScholarCrossref
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    2 Comments for this article
    EXPAND ALL
    NASAID use in pregnancy
    Robert James Carpenter, Jr MD JD | Baylor College of Medicine OB/GYN MFM
    The article is informative and disturbing in that since acetaminophen (Tylenol) use is discussed as stand alone exposure/effects, the same effects may well be attributable to the entire class of all NASAIDs much as was the case with the original increase of myocardial infarction that removed one specific NASAID from the market. At the time some of us believed that it would be seen in other agents of the class and subsequent research as shown that the same effect in similar degree occurs when one looks for the outcome.

    Since the pain relieving and especially the antipyretic effect of Tylenol is
    the most frequent reason for use of the drug, other confounders that were not looked at in the study such as degree of fever, type of pain for which agent chosen, and even the specific infection fever reduction was being sought for can not be analyzed.

    The database was prospective and collection robust so conclusion stands as it is. But now we have the problem of what drug is to be used as a substitute and from a strictly medical-legal issue since now that the association has been developed some lawyers will be looking at a class action suit using the data to extort monies from the various makers of drug including generics.

    All OBs and any primary care MD/DO using the drug will be required to discuss the study and its implications with patients prior to its use as will any provider/manufacturer of medication be wise to consider a \"black box\" warning of its use in pregnancy.

    Time will give us more insight into the repercussions of this observation.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    This article should be retracted immediately.
    Daniel Baldor | MS3 MD/MPH UMiami Miller School of Medicine
    This article should be retracted. There is no significance to the outcomes once the confounders of smoking or alcohol consumption during pregnancy (higher in the acetaminophen usage group), and maternal psychiatric illness (also higher in the acetaminophen usage group) are included in the analysis. This outcome was hidden in supplementary content (eTable 3) and we should all be worried that JAMA participates in this level of malfeasance.

    Most troubling is the language used by the authors to cover this fact up: “Inclusion of covariates did not change the RRs, although CIs were wider owing to the reduced sample size when
    covariates were included.” Noticeably absent from this statement is the fact that the “wider” CIs crossed 1.0 for every outcome.

    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    October 2016

    Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood: Evidence Against Confounding

    Author Affiliations
    • 1Medical Research Council (MRC) Integrative Epidemiology Unit (IEU) at the University of Bristol, University of Bristol, Bristol, United Kingdom
    • 2Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, Wales
    JAMA Pediatr. 2016;170(10):964-970. doi:10.1001/jamapediatrics.2016.1775
    Abstract

    Importance  Acetaminophen (paracetamol) is used by a large proportion of pregnant women. Research suggests that acetaminophen use in pregnancy is associated with abnormal fetal neurodevelopment. However, it is possible that this association might be confounded by unmeasured behavioral factors linked to acetaminophen use.

    Objective  To examine associations between offspring behavioral problems and (1) maternal prenatal acetaminophen use, (2) maternal postnatal acetaminophen use, and (3) partner’s acetaminophen use.

    Design, Setting, and Participants  From February 2015 to March 2016, we collected and analyzed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective birth cohort. We studied 7796 mothers enrolled in ALSPAC between 1991 and 1992 along with their children and partners.

    Exposures  Acetaminophen use was assessed by questionnaire completion at 18 and 32 weeks of pregnancy and when the child was 61 months old.

    Main Outcomes and Measures  Maternal reports of behavioral problems using the Strengths and Difficulties Questionnaire (SDQ) when the children were 7 years old. We estimated risk ratios for behavioral problems in children after prenatal, postnatal, and partner’s exposure to acetaminophen and mutually adjusted each association.

    Results  Maternal prenatal acetaminophen use at 18 (n = 4415; 53%) and 32 weeks of pregnancy (n = 3381; 42%) was associated with higher odds of having conduct problems (risk ratio [RR], 1.42; 95% CI, 1.25-1.62) and hyperactivity symptoms (RR, 1.31; 95% CI, 1.16-1.49), while maternal acetaminophen use at 32 weeks was also associated with higher odds of having emotional symptoms (RR, 1.29; 95% CI, 1.09-1.53) and total difficulties (RR, 1.46; 95% CI, 1.21-1.77). This was not the case for maternal postnatal (n = 6916; 89%) or partner’s (n = 3454; 84%) acetaminophen use. We found the associations between maternal prenatal acetaminophen use and all the SDQ domains unchanged even after adjusting for maternal postnatal or partner’s acetaminophen use.

    Conclusions and Relevance  Children exposed to acetaminophen prenatally are at increased risk of multiple behavioral difficulties, and the associations do not appear to be explained by unmeasured behavioral or social factors linked to acetaminophen use insofar as they are not observed for postnatal or partner’s acetaminophen use. Although these results could have implications for public health advice, further studies are required to replicate the findings and to understand mechanisms.

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