Maternal inflammation during pregnancy is associated with risk of ADHD in children at age 10

Julie B Rosenberg; Jens Richardt Møllegaard Jepsen; Parisa Mohammadzadeh; Astrid Sevelsted; Rebecca Vinding; Mikkel E Sørensen; David Horner; Kristina Aagaard; Birgitte Fagerlund; Susanne Brix; Nilofar Følsgaard; Ann-Marie M Schoos; Jakob Stokholm; Bo Chawes; Christos Pantelis; Søren Dalsgaard; Birte Y Glenthøj; Niels Bilenberg; Klaus Bønnelykke; Bjørn H Ebdrup

doi:10.1016/j.bbi.2023.10.023

Maternal inflammation during pregnancy is associated with risk of ADHD in children at age 10

Brain Behav Immun. 2024 Jan:115:450-457. doi: 10.1016/j.bbi.2023.10.023. Epub 2023 Oct 31.

Authors

Julie B Rosenberg¹, Jens Richardt Møllegaard Jepsen², Parisa Mohammadzadeh³, Astrid Sevelsted⁴, Rebecca Vinding⁴, Mikkel E Sørensen⁵, David Horner⁶, Kristina Aagaard⁶, Birgitte Fagerlund⁷, Susanne Brix⁸, Nilofar Følsgaard⁴, Ann-Marie M Schoos⁹, Jakob Stokholm¹⁰, Bo Chawes⁶, Christos Pantelis¹¹, Søren Dalsgaard¹², Birte Y Glenthøj¹³, Niels Bilenberg¹⁴, Klaus Bønnelykke⁶, Bjørn H Ebdrup¹³

Affiliations

¹ Center for Neuropsychiatric Schizophrenia Research (CNSR) & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark; Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address: [email protected].
² Center for Neuropsychiatric Schizophrenia Research (CNSR) & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark; Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.
³ Center for Neuropsychiatric Schizophrenia Research (CNSR) & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark; Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁴ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark.
⁵ Center for Neuropsychiatric Schizophrenia Research (CNSR) & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark.
⁶ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁷ Center for Neuropsychiatric Schizophrenia Research (CNSR) & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark; Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark; Department of Psychology, University of Copenhagen, Copenhagen, Denmark.
⁸ DTU, Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark.
⁹ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Slagelse Hospital, Slagelse, Denmark.
¹⁰ Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark; Department of Pediatrics, Slagelse Hospital, Slagelse, Denmark; Department of Food Science, University of Copenhagen, Denmark.
¹¹ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.
¹² Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark; National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark.
¹³ Center for Neuropsychiatric Schizophrenia Research (CNSR) & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Department of Child and Adolescent Mental Health Odense, Mental Health Services in the Region of Southern Denmark, University of Southern Denmark, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

PMID: 37914103
DOI: 10.1016/j.bbi.2023.10.023

Abstract

Introduction: Maternal inflammation during pregnancy may affect early neurodevelopment in offspring as suggested by preclinical and register data. However, clinical evidence for risk of aberrant neurodevelopment later in childhood is scarce. In the population-based COPSAC₂₀₁₀ mother-child cohort, we investigated associations between maternal inflammation levels during pregnancy and the risk of a diagnosis of ADHD as well as the load of ADHD symptoms in the children at age 10.

Methods: The COPSAC₂₀₁₀ cohort consists of 700 mother-child pairs followed prospectively since pregnancy week 24.Maternal high-sensitivity C-Reactive Protein (hs-CRP) level at week 24 of gestation was investigated in relation to child neurodevelopment by age 10 using logistic and linear regression models with extensive confounder adjustment, including socioeconomic status and maternal polygenic risk of ADHD. The children completed a comprehensive examination of neurodevelopment including categorical (i.e., diagnostic) and dimensional (i.e., symptom load) psychopathology using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) and parental rated ADHD-Rating Scale (ADHD-RS).

Results: A total of 604 (86 %) of the 700 children in the COPSAC₂₀₁₀ cohort participated in the COPSYCH visit at age 10. Sixty-five (10.8 %) fulfilled a research diagnosis of ADHD (16 girls and 49 boys). Higher maternal hs-CRP level in pregnancy at week 24 (median 5.4 mg/L) was significantly associated with increased risk for a diagnosis of ADHD, adjusted OR 1.40, 95 %CI (1.16-1.70), p = 0.001. Additionally, higher maternal hs-CRP was associated with increased ADHD symptom load in the entire cohort, reflected by ADHD-RS raw scores.

Discussion: These clinical data demonstrated a robust association of prenatal maternal inflammation assessed by hs-CRP with a diagnosis of ADHD by age 10. Moreover, maternal inflammation was associated with ADHD symptom load in the complete cohort. Identifying inflammation as an important marker will provide a potential target for future increased awareness and prevention during pregnancy thereby ultimately improving neurodevelopmental outcomes in children.

Keywords: ADHD; C-Reactive Protein; Inflammation; Prenatal exposures; Prevention.

MeSH terms

Attention Deficit Disorder with Hyperactivity* / etiology
C-Reactive Protein
Child
Female
Humans
Inflammation / complications
Male
Parents
Pregnancy
Prenatal Exposure Delayed Effects* / psychology

Substances

C-Reactive Protein