{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:42:00Z","timestamp":1760146920497,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Patient-Centered Outcomes Research Institute","award":["PCS-2018C1-11111"],"award-info":[{"award-number":["PCS-2018C1-11111"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background\/Objectives: In utero exposure to painkillers has raised concerns regarding its potential impact on neurodevelopmental disorders, such as autism spectrum disorder (ASD). This study investigates the association between in utero exposure to painkillers and trajectories of hyperactivity and emotional problems in children with and without ASD, separately. Methods: Data were drawn from 5107 participants enrolled in the Longitudinal Study of Australian Children. Emotional and behavioral problems were assessed using the Strengths and Difficulties Questionnaire at ages 4, 6, and 8 years. ASD diagnosis was determined based on parental self-report by age 12. To examine the association between the exposure and the outcomes, mixed linear models were applied to assess the impact of in utero exposure to painkillers on hyperactivity and emotional problems, controlling for sex, time, and other perinatal risk factors. The interaction term between exposure and time was included to evaluate the effect of exposure on the trajectory over time. Results: In utero exposure to painkillers did not significantly affect hyperactivity or emotional problem trajectories in children with ASD. However, in non-ASD children, painkiller exposure was associated with worsening emotional problems by age 8, with males being affected to a greater extent than females. Further, emotional problem scores increased over time by gender, reflecting developmental challenges in early childhood. Conclusions: These findings indicate that prenatal painkiller exposure is unlikely to be a major determinant of the severity of neurodevelopmental outcomes in autistic children, but its role in neurodevelopmental outcomes among neurotypical children warrants further investigation. Future research should prioritize precise exposure assessments and integrate multi-environment interactions to further elucidate the long-term impacts of prenatal painkiller use.<\/jats:p>","DOI":"10.3390\/children11121558","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T04:33:29Z","timestamp":1734928409000},"page":"1558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Association Between In Utero Exposure to Painkillers and Trajectories of Hyperactivity and Emotional Problems in Children with Autism Compared with Neurotypical Peers"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9739-7184","authenticated-orcid":false,"given":"Ping-I.","family":"Lin","sequence":"first","affiliation":[{"name":"Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW 2033, Australia"},{"name":"Department of Psychiatry and Behavioral Neuroscience, Saint Louis University, St. Louis, MO 63103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyi Shinn","family":"Khin","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James R.","family":"John","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW 2033, Australia"},{"name":"Academic Unit of Child and Adolescent Psychiatric Services, South Western Sydney Local Health District, Liverpool, NSW 2170, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3772-5745","authenticated-orcid":false,"given":"Adam K.","family":"Walker","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW 2033, Australia"},{"name":"Laboratory of ImmunoPsychiatry, Neuroscience Research Australia, Randwick, NSW 2031, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Chia","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Population Health, University of New South Wales, Sydney, NSW 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nawar","family":"Nayeem","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Neuroscience, Saint Louis University, St. Louis, MO 63103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erick","family":"Messias","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Neuroscience, Saint Louis University, St. Louis, MO 63103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e013372","DOI":"10.1136\/bmjopen-2016-013372","article-title":"Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: An updated analysis of the Quebec Pregnancy Cohort","volume":"7","author":"Zhao","year":"2017","journal-title":"BMJ Open"},{"key":"ref_2","first-page":"e167","article-title":"Risks of 23 specific malformations associated with prenatal exposure to 10 antiepileptic drugs","volume":"93","author":"Raguideau","year":"2019","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"648.e1","DOI":"10.1016\/j.ajog.2019.06.050","article-title":"In utero exposure to antibiotics and risk of congenital malformations: A population-based study","volume":"221","author":"Damkier","year":"2019","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1001\/jama.2017.3413","article-title":"Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy with Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit\/Hyperactivity Disorder in Offspring","volume":"317","author":"Sujan","year":"2017","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1097\/AOG.0000000000002579","article-title":"Prescription and Other Medication Use in Pregnancy","volume":"131","author":"Haas","year":"2018","journal-title":"Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/s41574-021-00553-7","article-title":"Paracetamol use during pregnancy\u2014A call for precautionary action","volume":"17","author":"Bauer","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e20163840","DOI":"10.1542\/peds.2016-3840","article-title":"Prenatal exposure to acetaminophen risk of ADHD","volume":"140","author":"Ystrom","year":"2017","journal-title":"Pediatrics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1002\/aur.1591","article-title":"Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study","volume":"9","author":"Liew","year":"2016","journal-title":"Autism Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1001\/jamapediatrics.2016.1775","article-title":"Association of acetaminophen use during pregnancy with behavioral problems in childhood: Evidence against confounding","volume":"170","author":"Stergiakouli","year":"2016","journal-title":"JAMA Pediatr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1038\/s41380-018-0321-0","article-title":"Big data approaches to decomposing heterogeneity across the autism spectrum","volume":"24","author":"Lombardo","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S2215-0366(16)30376-5","article-title":"Neurodevelopmental disorders","volume":"4","author":"Thapar","year":"2017","journal-title":"Lancet Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/S2352-4642(23)00127-X","article-title":"Association between the timing of childhood adversity and epigenetic patterns across childhood and adolescence: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort","volume":"7","author":"Lussier","year":"2023","journal-title":"Lancet Child. Adolesc. Health"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e197025","DOI":"10.1001\/jamanetworkopen.2019.7025","article-title":"Cognitive and Motor Outcomes of Children with Prenatal Opioid Exposure a Systematic Review and Meta-analysis","volume":"2","author":"Yeoh","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_14","unstructured":"Sanson, A.V., Nicholson, J., Ungerer, J., Zubrick, S., Wilson, K., Ainley, J., Berthelsen, D., Bittman, M., Broom, D., and Harrison, L. (2024, December 19). Introducing the Longitudinal Study of Australian Children. LSAC Discussion Paper. Available online: https:\/\/openresearch-repository.anu.edu.au\/server\/api\/core\/bitstreams\/9f3020a9-970f-43bc-b1a4-307e4dbbf8c5\/content."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/j.1469-7610.1997.tb01545.x","article-title":"The Strengths and Difficulties Questionnaire: A research note","volume":"38","author":"Goodman","year":"1997","journal-title":"J. Child. Psychol. Psychiatry"},{"key":"ref_16","first-page":"1","article-title":"A Systematic Review of Some Reliability and Validity Issues regarding the Strengths and Difficulties Questionnaire Focusing on Its Use in Out-of-Home Care","volume":"18","author":"Baviskar","year":"2020","journal-title":"J. Evid.-Based Soc. Work."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1176\/appi.ajp.160.11.1985","article-title":"Maternal smoking during pregnancy and attention deficit hyperactivity disorder symptoms in offspring","volume":"160","author":"Thapar","year":"2003","journal-title":"Am. J. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Jansone, K., Eichler, A., Fasching, P.A., Kornhuber, J., Kaiser, A., Millenet, S., Banaschewski, T., and Nees, F. (2023). Association of Maternal Smoking during Pregnancy with Neurophysiological and ADHD-Related Outcomes in School-Aged Children. Int. J. Environ. Res. Public. Health, 20.","DOI":"10.3390\/ijerph20064716"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1093\/ije\/dyaa001","article-title":"Using a cross-cohort comparison design to test the role of maternal smoking in pregnancy in child mental health and learning: Evidence from two UK cohorts born four decades apart","volume":"49","author":"Sellers","year":"2021","journal-title":"Int. J. Epidemiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.reprotox.2017.12.010","article-title":"Prenatal exposure to maternal smoking during pregnancy and attention-deficit\/hyperactivity disorder in offspring: A meta-analysis","volume":"76","author":"Dong","year":"2018","journal-title":"Reprod. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1037\/bul0000091","article-title":"Mental health of extremely low birth weight survivors: A systematic review and meta-analysis","volume":"143","author":"Mathewson","year":"2017","journal-title":"Psychol. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1001\/archgenpsychiatry.2011.138","article-title":"Early risk factors for hyperactivity-impulsivity and inattention trajectories from age 17 months to 8 years","volume":"68","author":"Bouvard","year":"2011","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1111\/jcpp.12949","article-title":"The role of birth weight on the causal pathway to child and adolescent ADHD symptomatology: A population-based twin differences longitudinal design","volume":"59","author":"Lim","year":"2018","journal-title":"J. Child. Psychol. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1097\/01.chi.0000246059.62706.22","article-title":"Birth weight and attention-deficit\/hyperactivity symptoms in childhood and early adolescence: A prospective Swedish twin study","volume":"46","author":"Hultman","year":"2007","journal-title":"J. Am. Acad. Child. Adolesc. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/jcpp.12299","article-title":"Birth weight as an independent predictor of ADHD symptoms: A within-twin pair analysis","volume":"56","author":"Pettersson","year":"2015","journal-title":"J. Child. Psychol. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e20171645","DOI":"10.1542\/peds.2017-1645","article-title":"Attention-deficit\/hyperactivity disorder and very preterm\/very low birth weight: A meta-analysis","volume":"141","author":"Franz","year":"2018","journal-title":"Pediatrics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.eurpsy.2015.03.005","article-title":"Maternal tobacco smoking in pregnancy and children\u2019s socio-emotional development at age 5: The EDEN mother-child birth cohort study","volume":"30","author":"Melchior","year":"2015","journal-title":"Eur. Psychiatry"},{"key":"ref_28","first-page":"S142","article-title":"Cognitive, psycho-social, and medical outcomes of very low birth weight infants at age 10\u201314 years in Ireland","volume":"22","author":"Healy","year":"2013","journal-title":"Eur. Child. Adolesc. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.acap.2020.05.010","article-title":"The Inter-Relationships of Extremely Low Birth Weight, Asthma, and Behavior: A Study of Common Cause, Mediation, and Moderation","volume":"20","author":"Litt","year":"2020","journal-title":"Acad. Pediatr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"448","DOI":"10.22237\/jmasm\/1257034080","article-title":"Impact of rank-based normalizing transformations on the accuracy of test scores","volume":"8","author":"Solomon","year":"2009","journal-title":"J. Mod. Appl. Stat. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Balalian, A.A., Graeve, R., Richter, M., Fink, A., Kielstein, H., Martins, S.S., Philbin, M.M., and Factor-Litvak, P. (2023). Prenatal exposure to opioids and neurodevelopment in infancy and childhood: A systematic review. Front. Pediatr., 11.","DOI":"10.3389\/fped.2023.1071889"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s40264-021-01080-0","article-title":"Association Between Prenatal Opioid Exposure and Neurodevelopmental Outcomes in Early Childhood: A Retrospective Cohort Study","volume":"44","author":"Wen","year":"2021","journal-title":"Drug Saf."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1097\/ANA.0000000000000876","article-title":"Prenatal Opioid Exposure and Neurodevelopmental Outcomes","volume":"35","author":"Lee","year":"2023","journal-title":"J. Neurosurg. Anesthesiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e20190128","DOI":"10.1542\/peds.2019-0128","article-title":"Prenatal opioid exposure: Neurodevelopmental consequences and future research priorities","volume":"144","author":"Conradt","year":"2019","journal-title":"Pediatrics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e2222425","DOI":"10.1001\/jamanetworkopen.2022.22425","article-title":"Analysis of Prenatal Exposure to Opioid Analgesics and Scholastic Skills in Children in Fifth Grade in Norway","volume":"5","author":"Lupattelli","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kwok, J., Luedecke, E., Hall, H.A., Murray, A.L., and Auyeung, B. (2022). Analgesic drug use in pregnancy and neurodevelopment outcomes: An umbrella review. Neurosci. Biobehav. Rev., 136.","DOI":"10.1016\/j.neubiorev.2022.104607"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2124324","DOI":"10.1001\/jamanetworkopen.2021.24324","article-title":"Association of Timing and Duration of Prenatal Analgesic Opioid Exposure with Attention-Deficit\/Hyperactivity Disorder in Children","volume":"4","author":"Lupattelli","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/s00702-016-1556-z","article-title":"Developmental exposure to acetaminophen does not induce hyperactivity in zebrafish larvae","volume":"123","author":"Reuter","year":"2016","journal-title":"J. Neural Transm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1093\/aje\/kwy086","article-title":"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","volume":"187","author":"Masarwa","year":"2018","journal-title":"Am. J. Epidemiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3345\/cep.2022.01319","article-title":"Acetaminophen causes neurodevelopmental injury in susceptible babies and children: No valid rationale for controversy","volume":"67","author":"Zhao","year":"2023","journal-title":"Clin. Exp. Pediatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1476-069X-12-41","article-title":"Prenatal and perinatal analgesic exposure and autism: An ecological link","volume":"12","author":"Bauer","year":"2013","journal-title":"Environ. Health"},{"key":"ref_42","first-page":"204","article-title":"The Development of Emotional and Behavioral Control in Early Childhood:Heterotypic Continuity and Relations to Early School Adjustment","volume":"3","author":"Chang","year":"2015","journal-title":"J. Child. Adolesc. Behav."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9","DOI":"10.5409\/wjcp.v7.i1.9","article-title":"Behavioural and emotional disorders in childhood: A brief overview for paediatricians","volume":"7","author":"Ogundele","year":"2018","journal-title":"World J. Clin. Pediatr."},{"key":"ref_44","unstructured":"Ozerova, E., Martinsone, B., Cefai, C., and Conte, E. (2022, January 29\u201331). Social-Emotional Skills, Behavioural Problems and Learning Outcomes of Elementary School Children. Proceedings of the ATEE 2022 Annual Conference, Riga, Latvia."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1080\/01443410.2015.1034090","article-title":"Emotional development among early school-age children: Gender differences in the role of problem behaviours","volume":"36","author":"Maguire","year":"2016","journal-title":"Educ. Psychol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Mkhitaryan, M., Avetisyan, T., Mkhoyan, A., Avetisyan, L., and Yenkoyan, K. (2024). A case\u2013control study on pre-, peri-, and neonatal risk factors associated with autism spectrum disorder among Armenian children. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-63240-3"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bpsgos.2023.09.008","article-title":"Inflammatory Conditions During Pregnancy and Risk of Autism and Other Neurodevelopmental Disorders","volume":"4","author":"Croen","year":"2024","journal-title":"Biol. Psychiatry Glob. Open Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13229-017-0121-4","article-title":"Environmental risk factors for autism: An evidence-based review of systematic reviews and meta-analyses","volume":"8","author":"Modabbernia","year":"2017","journal-title":"Mol. Autism"}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/11\/12\/1558\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:58:10Z","timestamp":1760115490000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/11\/12\/1558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,23]]},"references-count":48,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["children11121558"],"URL":"https:\/\/doi.org\/10.3390\/children11121558","relation":{},"ISSN":["2227-9067"],"issn-type":[{"type":"electronic","value":"2227-9067"}],"subject":[],"published":{"date-parts":[[2024,12,23]]}}}