Elevated maternal interleukin 6 (IL-6) during pregnancy has been associated with adverse fetal brain development and neurodevelopmental disorders, which often involve executive functioning (EF) impairments. However, the association between maternal IL-6 levels during pregnancy and EF remains largely unexplored.

The COPSYCH study is based on the prospective COPSAC2010 birth cohort of 700 mother-child pairs, recruited during pregnancy. The children’s executive functioning was assessed at age 10 using: (i) the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) parental questionnaire, and (ii) a comprehensive neuropsychological test battery. Maternal blood levels of IL-6 and hs-CRP were measured at gestational week 24. Associations between IL-6 (main analysis) and hs-CRP (secondary analysis) and EF in children at age 10 were investigated with regression models with extensive confounder adjustment.

Six hundred and four children (86% of the cohort) completed the 10-year follow-up. Higher maternal IL-6 levels were significantly associated with less efficient parental-rated executive functioning in the children: BRIEF-2 Global Executive Composite score (p = 0.003), Behavior Regulation Index (p = 0.005), Emotion Regulation Index (p=0.04), and Cognitive Regulation Index (p=0.007). Interaction analysis with sex was significant (p-value=0.01) and exploratory analyses showed that IL-6 associations to BRIEF-2 were solely driven by boys. Associations between IL-6 and neuropsychological tests, as well as associations between hs-CRP and EF outcomes, were non-significant.

IL-6 during pregnancy was associated with less efficient everyday EF in children at age 10. If replicated, preventive strategies targeting inflammation in pregnancy may ameliorate adverse cognitive outcomes in offspring.

The prevalence of youth anxiety and depression has increased globally, with limited causal explanations. Long-term physical health conditions (LTCs) affect 20–40% of youth, with rates also rising. LTCs are associated with higher rates of youth depression and anxiety; however, it is uncertain whether observed associations are causal or explained by unmeasured confounding or reverse causation.

Using data from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and Norwegian National Patient Registry, we investigated phenotypic associations between childhood LTCs, and depression and anxiety diagnoses in youth (<19 years), defined using ICD-10 diagnoses and self-rated measures. We then conducted two-sample Mendelian Randomization (MR) analyses using SNPs associated with childhood LTCs from existing genome-wide association studies (GWAS) as instrumental variables. Outcomes were: (i) diagnoses of major depressive disorder (MDD) and anxiety disorders or elevated symptoms in MoBa, and (ii) youth-onset MDD using summary statistics from a GWAS in iPSYCH2015 cohort.

Having any childhood LTC phenotype was associated with elevated youth MDD (OR = 1.48 [95% CIs 1.19, 1.85], p = 4.2×10−4) and anxiety disorder risk (OR = 1.44 [1.20, 1.73], p = 7.9×10−5). Observational and MR analyses in MoBa were consistent with a causal relationship between migraine and depression (IVW OR = 1.38 [1.19, 1.60], pFDR = 1.8x10−4). MR analyses using iPSYCH2015 did not support a causal link between LTC genetic liabilities and youth-onset depression or in the reverse direction.

Childhood LTCs are associated with depression and anxiety in youth, however, little evidence of causation between LTCs genetic liability and youth depression/anxiety was identified from MR analyses, except for migraine.