Maternal Inflammatory Proteins in Pregnancy and Neurodevelopmental Disorders at Age 10 Years
Authors: Tingting Wang, Parisa Mohammadzadeh, Jens Richardt Møllegaard Jepsen, Jonathan Thorsen, Julie Bøjstrup Rosenberg, Cecilie Koldbæk Lemvigh, Nicklas Brustad, Liang Chen, Mina Ali, Rebecca Vinding, Casper-Emil Tingskov Pedersen, María Hernández-Lorca, Birgitte Fagerlund, Birte Y. Glenthøj, Niels Bilenberg, Jakob Stokholm, Klaus Bønnelykke, Bo Chawes, Bjørn H. Ebdrup
Journal: JAMA Psychiatry (2025)

IMPORTANCE Maternal inflammation during pregnancy has been associated with an increased risk of neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD) and autism, and cognitive deficits in early childhood. However, little is known about the contributions of a wider range of inflammatory proteins to this risk. OBJECTIVE To determine whether maternal inflammatory proteins during pregnancy are associated with the risk of NDDs and executive functions (EF) in middle childhood and to identify protein patterns associated with NDDs and EF. DESIGN, SETTING, AND PARTICIPANTS This was a 10-year follow-up cohort study of the Danish Copenhagen Prospective Studies on Asthma 2010 mother-child birth cohort, using plasma samples collected at week 24 in pregnancy, where 92 inflammatory proteins were assessed. NDDs and EF were assessed in the offspring at age 10 years, between January 2019 and December 2021. Mother-offspring dyads with available maternal prenatal inflammatory proteins during pregnancy and offspring NDD psychopathology data at follow-up were included. Data analyses took place between December 2023 and August 2024. EXPOSURES Levels of 92 inflammatory proteins from panel collected at week 24 during pregnancy. MAIN OUTCOMES AND MEASURES Categorical and dimensional psychopathology of NDDs (primary outcome) and EF (secondary outcome). RESULTS A total of 555 mothers (mean [SD] age, 32.4 [4.3] years) and their children (285 male [51%]) were included. The principal component analysis showed that higher levels of maternal inflammatory proteins depicted in principal component 1 were associated with a higher risk of any NDD (OR, 1.49; 95% CI, 1.15-1.94; P = .003), particularly autism (OR, 2.76; 95% CI, 1.45-5.63; P = .003) and ADHD with predominantly inattentive presentation (OR, 1.57; 95% CI, 1.05-2.39; P = .03). The single protein analysis showed that 18 of 92 proteins reached false discovery rate (FDR) 5% significance after adjustment. Vascular endothelial growth factor A, C-C motif chemokine ligand, CD5, interleukin 12B, fibroblast growth factor-23, and monocyte chemoattractant protein-1 emerged as top proteins associated with risk of NDDs. The sparse partial least squares approach identified 34 proteins associated with any NDD, and 39 with ADHD with predominantly inattentive presentation. There were no associations with EF after FDR correction. CONCLUSIONS AND RELEVANCE The maternal inflammatory proteome during pregnancy was associated with NDDs risks in offspring at age 10 years. Further research is warranted to elucidate the specific pathways involving these proteins during pregnancy that could be targeted with prevention strategies to reduce risk of NDDs in children.