By Parisa Mohammadzadeh
Chairperson: Professor Anne Amalie Elgaard Thorup, Denmark
Opponent: Professor Juha Veijola University of Oulu, Finland
Opponent:Dr Gisela Sugranyes University of Barcelona, Spain
Summary
Neurodevelopmental disorders (NDDs) and impaired executive functioning (EF) are potentially extensive and have serious consequences for the quality of life of children and adolescents. These disorders, encompass a group of conditions that arise early in life and include Autism Spectrum Disorders (ASD) and Attention-Deficit/Hyperactive Disorder (ADHD), which are among the most common. Our current understanding of environmental factors that could contribute to the development of these conditions is somewhat limited, indicating a need for further research in this field. Thus, studies that can aid in uncovering why children develop these conditions are necessary for future health.
There is a theoretical indication that the perinatal period is where the foetus is particularly vulnerable and susceptible to various exposures, including inflammation. This also means that this period is a window of opportunity where we may modulate this influence and thus possibly prevent the development of neurodevelopmental disorders and impaired cognitive abilities.
This thesis consists of three Papers, based on data from the COPSAC2010 birth cohort, with 700 mother-child pairs followed prospectively from week 24 of pregnancy through 14 visits until the 10-year visit. Deep phenotyping throughout the years has yielded a robust dataset that provided excellent opportunities for investigation of this.
The primary purpose of the COPSAC2010 cohort was to examine the effect of two doubleblinded randomised trials where mothers during pregnancy received either fish oil, high-dose vitamin D, or placebo and the development of asthma and wheezing by the age of five.
Additionally, neurodevelopment was also a predetermined secondary outcome for the COPSAC2010 cohort. The COPSYCH study, based on the COPSAC2010 cohort, is a collaborative effort between COPSAC and CNSR. Its primary aim was to investigate and assess the impact of early life exposures on psychopathological, cognitive, and brain structure and physiology in 10-year-old children.
A thorough examination of neurodevelopment was conducted at the 10-year visit where children’s psychopathology, cognitive abilities, and brain structure and function were investigated. This was done through extensive testing, interviews, questionnaires, and MRI
scanning of the brain.
The purpose of this thesis is to investigate the effect of inflammation in week 24 of pregnancy on children’s psychopathology, neurodevelopmental disorders, and cognition, specifically executivefunction, at the age of 10. We hypothesise that inflammation during pregnancy affects the foetal brain and therefore increases the risk of aberrant neurodevelopment later in life.
Paper I
Paper I is a study protocol outlining the background, purpose, and methodology of the COPSYCH study. It describes the cognitive assessment battery, the investigation of psychopathology, and the description of MRI modalities.
Paper II
Paper II investigates whether increased inflammation, specifically interleukin 6 (IL-6), in week 24 of pregnancy, is associated with impaired executive function (EF) in the children at 10 years of age. The results showed that elevated levels of IL-6 were associated with less efficient executive functions, solely among boys, even after thorough adjustment for covariates. Children with NDD exhibit particularly pronounced deficits in EF. A sensitivity analysis revealed that increased IL-6 levels were associated with less efficient EF across all children in
the study, reflecting the general population. Additionally, further sensitivity analysis showed no association with intelligence.
Paper III
Paper III utilised blood samples from week 24 of pregnancy to construct an inflammatory proteomic profile and examined its association with neurodevelopmental disorders and executive functions in offspring at age 10. A strong association was found between maternal inflammatory proteome and NDDs, but no associations found with EF passed multiple testing.
Conclusion
In summary, these studies indicate that inflammation in the form of elevated levels of inflammatory proteins during pregnancy increases the risk of the child developing NDDs, as well as less efficient executive functions at 10 years of age. This suggests the possibility of considering efforts to reduce exposures that increase inflammation in pregnant mothers during this vulnerable period.
