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prenatal acetaminophen use and otucomes in children
Prenatal acetaminophen use and outcomes in children Society for Maternal-Fetal Medicine (SMFM) Publications Committee The practice of medicine continues to evolve, and individual circumstances will vary. This publication re ﬂ ects information available at the time of its submission for publication and is neither designed nor intended to establish an exclusive standard of perinatal care. This publication is not expected to re ﬂ ect the opinions of all members of the Society for Maternal-Fetal Medicine. Acetaminophen is the most widely used medicine dur- ing pregnancy.1 While the rate of use in pregnancy is dif ﬁ cult to determine because it is an over-the-counter medication, large surveys have reported that 40e65% of pregnant women use acetaminophen at some time during their pregnancy. The most common uses are for headache and fever.2 Acetaminophen crosses the placenta relatively easily and has been reported in umbilical cord blood after maternal administration in labor.3 While largely considered to be safe during pregnancy, a few recently published observational studies have reported an association between prenatal acetaminophen use and potential increased risk for adverse neurological outcomes in childhood. The purpose of this Society for Maternal-Fetal Medicine (SMFM) Publications Committee statement is to review the nature and ﬁ ndings of these recent studies and put them into context with the available scienti ﬁ c literature to provide guidance to practicing obstetric care providers as they discuss these issues with their patients. Two retrospective cohort studies published within the last year have reported an association between prenatal acet- aminophen use and an increased risk for adverse neuro- logical outcomes in childhood. Stergiakouli et al4 studied therelationshipbetweenperinatalacetaminophenexposure and behavioral disorders in children, including attention de ﬁ citehyperactivity disorder (ADHD), using the Avon Longitudinal Study of Parents and Children. In this study, women (n ¼ 7796) were asked at 18 and 32 weeks of gestation about acetaminophen use in the previous 3 months. Childhood behavioral issues were assessed at age 7 years by the Strengths and Dif ﬁ culties Questionnaire. Maternal prenatal acetaminophen use was associated with higher odds of having conduct problems (risk ratio [RR], 1.42; 95% con ﬁ dence interval [CI], 1.25-1.62) and hyper- activity symptoms (RR, 1.31; 95% CI, 1.16e1.49). Limitations of this study include the fact that acetamino- phen use was self-reported (eg, potential for recall bias) and that there was no information on dosage and duration of the exposure. Finally, the outcome was measured at one point at age 7 years using a parental survey rather than assess- ment by health care professionals. Another recent study was based on data from the Danish National Birth Cohort in which women with singleton live births (n ¼ 64,322) were prospectively asked about acet- aminophen use in computer-assisted telephone interviews at 12 and 30 weeks of gestation as well as at 6 months postpartum.5 Review of hospital records and psychiatric registries were performed to identify diagnoses of autistic spectrum disorder (ASD). In this study, any prenatal use of acetaminophen was associated with an increased risk for ASDwithahyperkineticdisorder(hazardratio,1.51;95%CI, 1.19e1.92) among the offspring but not ASD without hy- perkinetic disorder (hazard ratio, 1.07; 95% CI, 0.92e1.24).5 Thereare3otherlargeretrospectivecohortstudiesthathave been published in the last few years (2013e2014) that exam- ined the potential association between maternal acetamino- phen use and ADHD in their offspring; all reported a weak association.6-8 However, each of these studies was limited by maternal self-report of acetaminophen use, lack of quanti ﬁ - cation of the doses, and measurement of the outcome using questionnaires assessing child and adolescent behavior. Another recently published observational study, a longi- tudinal study of maternal analgesic use and the subsequent occurrence of psychotic symptoms and schizophrenia in theirchildren,foundnoassociationwithacetaminophenuse but did ﬁ nd a positive association with aspirin use (adjusted odds ratio, 2.79; 95% CI, 1.27e6.07).9 On Jan. 9, 2015, the Food and Drug Administration announcedithasreviewedthepossiblerisksofpainmedicine useduringpregnancyandstated:“Basedonourevaluationof these studies, we believe that the weight of evidence is inconclusive regarding a possible connection between acet- aminophen use in pregnancy and ADHD in children.”10 They determined that the existing studies had ﬂ awed designs and the results were con ﬂ icted, precluding any Corresponding author: The Society for Maternal-Fetal Medicine Publications Committee. email@example.com B14 MARCH 2017 SMFM Statement smfm.org reliable conclusions about maternal acetaminophen use and the occurrence of ADHD.10 Two systematic reviews of the existing studies have both determined that evidence is insuf ﬁ cient to conclude that there is an association between maternal acetaminophen use and ADHD in offspring.2,11 While correlating exposures during pregnancy with child- hood outcomes is problematic, it is especially dif ﬁ cult with regard to neurobehavioral disorders. The de ﬁ nition and diagnosis of these illnesses, especially ADHD, continues to evolve.2 Furthermore, because the cause or causes of ADHD are unknown, there is the potential for other prenatal and postnatal confounders, such as environmental exposures and genetic predisposition, that these retrospective analyses are not able to measure.12-14 Finally, drawing conclusions on teratogenicity of a drug or other exposure based on retro- spective cohorts or birth defect registries requires extreme caution. Such studies have inherent methodological limita- tions, including the inability to determine or control for all potential confounders as well as recall bias, interview bias, and failure to adjust for multiple testing.15,16 The SMFM Publications Committee has reviewed these new studies along with the prior literature including the drug safety communication from the Food and Drug Adminis- tration. Similar to prior studies reporting an association between prenatal acetaminophen and increased odds for childhood neurobehavioral issues, these newer studies have signi ﬁ cant methodological and design limitations. Based on our evaluation of these studies, we believe that the weight of evidence is inconclusive regarding a possible causal relationship between acetaminophen use and neu- robehavioral disorders in the offspring. As with all medica- tion use during pregnancy, communication regarding the risks versus the bene ﬁ ts of prescription and over-the- counter medications use should occur between patient andprovider.TheSMFMPublications Committeecontinues to advise that acetaminophen be considered a reasonable and appropriate medication choice for the treatment of pain and/or fever during pregnancy. n REFERENCES 1. Chambers C. Over-the-counter medications: risk and safety in preg- nancy. Semin Perinatol 2015;39:541-4. 2. Hoover RM, Hayes VA, Erramouspe J. Association between prenatal acetaminophen exposure and future risk of attention de ﬁ cit/hyperactivity disorder in children. Ann Pharmacother 2015;49:1357-61. 3. Levy G, Garrettson LK, Soda DM. Evidence of placental transfer of acetaminophen (letter). Pediatrics 1975;55:895. 4. Stergiakouli E, Thapar A, Davey Smith G. Association of acetaminophen use during pregnancy with behavioral problems in childhood: evidence against confounding. JAMA Pediatr 2016;170:964-70. 5. Liew Z, Ritz B, Virk J, Olsen J. Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: a Danish national birth cohort study. Autism Res 2016;9:951-8. 6. 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;42:1702-13. 7. Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use duringpregnancy,behavioralproblems, andhyperkineticdisorders.JAMA Pediatr 2014;168:313-20. 8. Thompson JM, Waldie KE, Wall CR, Murphy R, Mitchell EA. Auckland Birthweight Collaborative Study Group. Associations between acetamin- ophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years. PLoS One 2014;9:e108210. 9. Gunawardana L, Zammit S, Lewis G, et al. Examining the associa- tion between maternal analgesic use during pregnancy and risk of psychotic symptoms during adolescence. Schizophr Res 2011;126: 220-5. 10. Food and Drug Administration, Department of Health and Human Services. Drug Safety Communications. FDA has reviewed possible risks of pain medication during pregnancy. Jan. 9, 2015. Available at: http:// www.fda.gov/Drugs/DrugSafety/ucm429117.htm. Accessed Dec. 14, 2016. 11. Andrade C. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-de ﬁ cit/hyperactivity disorder in the offspring.J Clin Psychiatr 2016;77:e312-4. 12. Suades-González E, Gascon M, Guxens M, Sunyer J. Air pollution and neuropsychological development: a review of the latest evidence. Endo- crinology 2015;156:3473-82. 13. Ethier AA, Muckle G, Jacobson SW, Ayotte P, Jacobson JL, Saint- Amour D. Assessing new dimensions of attentional functions in children prenatally exposed to environmental contaminants using an adapted Posner paradigm. Neurotoxicol Teratol 2015;51:27-34. 14. Verner MA, Hart JE, Sagiv SK, Bellinger DC, Altshul LM, Korrick SA. Measured prenatal and estimated postnatal levels of polychlorinated biphenyls (PCBs) and ADHD-related behaviors in 8-year-old children. Environ Health Perspect 2015;123:888-94. 15. Poletta FA, López Camelo JS, Gili JA, Leoncini E, Castilla EE, Mastroiacovo P. Methodological approaches to evaluate teratogenic risk using birth defect registries: advantages and disadvantages. PLoS One 2012;7:e46626. 16. Källén BA. Methodological issues in the epidemiological study of the teratogenicity of drugs. Congenit Anom (Kyoto) 2005;45:44-51. All authors and committee members have ﬁ led a con ﬂ ict of interest disclosuredelineatingpersonal,professional,and/orbusinessinterests that might be perceived as a real or potential con ﬂ ict of interest in relation to this publication. Any con ﬂ icts have been resolved through a process approved by the Executive Board. The Society for Maternal- Fetal Medicine has neither solicited nor accepted any commercial involvement in the development of the content of this publication. This document has undergone an internal peer review through a multilevel committee process within the Society for Maternal-Fetal Medicine (SMFM). This review involves critique and feedback from the SMFM Publications and Risk Management Committees and ﬁ nal approval by the SMFM Executive Committee. SMFM accepts sole responsibility for document content. SMFM publications do not un- dergoeditorialand peer reviewby theAmericanJournalof Obstetrics& Gynecology. The SMFM Publications Committee reviews publications every 18-24 months and issues updates as needed. Further details regarding SMFM Publications can be found at www.smfm.org/ publications. All questions or comments regarding the document should be referred to the SMFM Publications Committee at firstname.lastname@example.org. smfm.org SMFM Statement ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2017.01.021 MARCH 2017 B15 er of acetaminophen (letter). Pediatrics 1975;55:895. 4. Stergiakouli E, Thapar A, Davey Smith G. Association of acetaminophen use during pregnancy with behavioral problems in childhood: evidence against confounding. JAMA Pediatr 2016;170:964-70. 5. Liew Z, Ritz B, Virk J, Olsen J. Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: a Danish national birth cohort study. Autism Res 2016;9:951-8. 6. 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;42:1702-13. 7. Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use duringpregnancy,behavioralproblems, andhyperkineticdisorders.JAMA Pediatr 2014;168:313-20. 8. Thompson JM, Waldie KE