Elevated Gestational IL-13 During Fetal Development Is Associated With Hyperactivity and Inattention in Eight-Year-Old Children

Abstract

Maternal immune activation (MIA) during fetal development leads to behavioral and psychological disorders in the offspring. Concomitantly, insufficient supply of polyunsaturated fatty acids (PUFAs) is suspected to contribute to early neuronal maldevelopment due to the immune modulatory capabilities of PUFAs. However, human data are missing considering both of these aspects and their impact on children's behavioral outcomes. In line, this study aimed to elucidate the influence of gestational cytokines and PUFA-containing lipids during late pregnancy on behavioral sequelae in childhood, particularly focusing on an immune activation shaped by a history of maternal atopic diseases instead of a pathogen-mediated immune response. Based on the prospective mother-child cohort LINA we assessed the unstimulated blood cytokine profiles and concentrations of PUFA-containing lipids of 293 mothers at the 34th week of pregnancy. Maternal history of atopic diseases was obtained from questionnaires and behavior in eight-year-old children was assessed by the standardized Strength and Difficulties Questionnaires (SDQ) generating scores for hyperactivity/inattention, emotional symptoms, conduct problems, and peer relationship problems. Elevated IL-13 increased the risk for the child to show behavioral difficulties, in particular, hyperactive/inattentive behavior [adj. OR (95% CI): 2.47 (1.51–4.02), n = 255 vs. 38] at the age of eight years. Although the presence of maternal atopic dermatitis (AD) was associated with increased gestational IL-13 concentrations [adj. MR (95% CI): 1.17 (1.04–1.32)], no effect on children's behavioral difficulties was observed. However, a decrease in the PUFA containing lipid species PC aa C38:6 was not only associated with an increased gestational IL-13 concentration but also mediated the indirect effect of low PC aa C38:6 concentrations on children's abnormal behavior independent of maternal AD. We additionally assessed whether maternal IL-13 and PC aa C38:6 concentrations translate their effect by altering children's cord blood PC aa C38:6 and IL-13. While also the children's cord blood IL-13 was related to children's behavior, no effect of children's PC aa C38:6 was observed. This is the first study demonstrating that elevated gestational IL-13 increases the risk for children to develop behavioral difficulties. Analyses suggest that a reduced supply of gestational PC aa C38:6 contributes to elevated gestational IL-13 leading to behavioral sequelae in the offspring.

Associations Between Eczema and Attention Deficit Hyperactivity Disorder Symptoms in Children

“…In our study, however, we observed no differences in maternal or cord blood cytokines between children with and without eczema, nor between children with and without ADHD symptoms. Our findings are contrary to results reported by other studies ( 36 , 37 ). A possible reason for the different results may be that we assayed cord blood without stimulation and cord blood levels of IFNγ without stimulation are generally low ( 38 ).…”

“…Another reason for the absence of differences in maternal or cord cytokines between children with and without eczema, nor between children with and without ADHD symptoms that we observed may be due to limited immune profiling. While the Newborn Epigenetics Study and LINA cohort reported associations between maternal IL-12p70, IL-17A, IL-1β, and IL-13 levels and child neurodevelopment ( 36 , 37 ), we did not measure these cytokines. We also assayed cytokines from maternal blood during pregnancy and cord blood which is not indicative of subsequent inflammation that may be brought about by gut microbiome dysbiosis that we have observed in children with eczema as well as in children with ADHD.…”

Primate Models as a Translational Tool for Understanding Prenatal Origins of Neurodevelopmental Disorders Associated With Maternal Infection

“…Thus, the complex cascade of changes associated with maternal infection and the subsequent maternal immune response ( 7 ) is uniquely positioned to influence the developing fetal brain. Even in the absence of an acute inflammatory event triggered by infection, variation in maternal cytokine levels during pregnancy have been associated with offspring neurobehavioral outcomes, including early alterations in brain growth, functional connectivity, behavioral development ( 8 , 9 , 10 , 11 , 12 ), and long-lasting dysregulation of stress response circuitry ( 13 ). Collectively, these studies suggest that changes in maternal-fetal immune environment during pregnancy can have long-lasting consequences, ranging from subtle differences in offspring brain and behavioral development to severe NDDs.…”

Immune activity at birth and later psychopathology in childhood

“…In this context, the type of biological matrix elected to measure cytokine concentrations as proxies for immune activity at birth is critical. Most studies have relied on DBS collected from the neonate several hours or days after birth ( Abdallah et al., 2013 ; Ghassabian et al., 2018 ; Heuer et al., 2019 ; Krakowiak et al., 2017 ; Mizejewski et al., 2013 ; Nelson et al., 2006 ; Skogstrand et al., 2019 ; Thürmann et al., 2019 ; Zerbo et al., 2014 ). In contrast, we have measured cytokine levels in CBS, i.e.…”