By Julie Rosenberg
Summary
Chair person: Michael Eriksen Benros
Opponent: Alexandra Havdahl
Opponent: Marlene Briciet Lauritsen
ABSTRACT
The incidence of psychiatric diagnoses among children and adolescents in Denmark is increasing, with 15% having received a psychiatric diagnosis by the age of 18. This incidence is based on data from the secondary sector, indicating that the true number is likely even higher due to a significant number being assessed by private practitioners of psychology and psychiatry. Simultaneously, various studies including Danish longitudinal national school surveys, report a decline in mental well-being, also among children without psychiatric diagnoses. It is a heated debate to what extend the aforementioned data reflects a true increase in incidence of mental disorders, improved identification due to beter diagnostic practice, an increased focus on mental well-being and health, societal changes making it more difficult to “fit in” if one is not entirely “neurotypical,” or a combination of all these factors. Thus, more research and knowledge of the development in prevalence and incidence are warranted, because in the absence of data, answers to this complex issue will be based on opinions, personal narratives, and political agendas.
Psychiatric disorders otien persist throughout life, severely affecting the individual, the surrounding family, social circles, and society at large. Therefore, research in preventive strategies is highly relevant and important.
This PhD thesis focuses on neurodevelopmental disorders, specifically ADHD and Autism Spectrum Disorder (ASD). Both ADHD and ASD likely have foundations laid, to a large extent, before birth but disentangling the impact of early risk factors is inherently challenging. While genetic predisposition is the most important known risk factor, environmental factors also play a role. Examples include premature birth, low birth weight, exposure to pollutants, e.g. lead, elevated maternal BMI, and proxy markers for low socioeconomic status, especially parental educational level, and household income.
This thesis investigates two additional environmental exposures thought to have influence early neurodevelopment: i) exposure to inflammation which is believed to have a negative effect and ii) exposure to omega-3 fatty acids, specifically DHA and EPA which are believed to have a positive effect. The studies in this PhD are based on the COPSAC2010 cohort, a population-based cohort of 700 mother-child pairs followed continuously from gestational week 24, enabling deep phenotyping of the cohort and allowing for detailed statistical adjustments for confounding factors.
Focus for the 10-year follow-up of the COPSAC2010 cohort was neurological development, which has been a pre-specified secondary outcome since the beginning of the cohort. Neurological development is reflected by psychopathology and neurocognition, as well as brain structure and function assessed through Magnetic Resonance Imaging (MRI).
Paper I is the study protocol for the COPSYCH 10-year follow-up outlining the background, aims and methods.
Paper II investigated whether maternal inflammation, measured by High-sensitivity C- Reactive Protein (Hs-CRP) in a blood sample in the 24th week of gestation, was associated with the risk of ADHD in 10-year-old children. Results showed an increased risk of ADHD as well as ADHD symptoms with rising Hs-CRP levels during pregnancy and were robust for extensive confounder adjustment. Sub-analyses showed that the association to ADHD was still robust atier excluding mother-child pairs with maternal hs-CRP level > 50 mg/L indicating acute viral or bacterial infections. This illustrates that the association can not solely be atributed to acute infections but appears to be driven also via systemic low-grade inflammation.
Paper III had a twofold aim: i) to examine if maternal blood levels of omega-3 faty acids (DHA+EPA) in gestational week 24 was associated with the risk of ADHD and ASD diagnoses and symptoms/traits in 10-year-old children, and ii) to investigate if fish oil supplementation (2.4 g daily from the 24th week of gestation to 1 week post-partum vs. placebo) in a randomized clinical trial affected the occurrence and severity of neurodevelopmental psychopathology in children 10 years later. The observational part of the study indicated that increasing blood levels of DHA+EPA in pregnant women in gestational week 24 were protective against developing ADHD and ASD in their children. However, these associations were no longer statistically significant atier adjusting for confounders, suggesting other factors play a more significant role. Regarding the second part of the hypothesis, the study overall found that fish oil supplementation in a randomised clinical design did not significantly impact the risk of developing ADHD or ASD. Secondary analyses, however, suggested that fish oil supplementation reduced the risk specifically for the predominantly inattentive presentation of ADHD.
In summary, we found prenatal exposure to increasing levels of inflammation to be associated with an elevated risk of ADHD in children 10 years later. Fish oil supplementation in the third trimester, investigated in a randomized controlled trial design, did not appear to be protective against the development of ADHD and ASD. However, it may reduce the risk specifically for the predominantly inatentive presentation of ADHD.
Omega-3 faty acids, notably EPA, are known to exert anti-inflammatory properties, thus early inflammation -or mitigation hereof- is an overarching theme of this thesis. Both inflammation and omega-3 faty acids are potentially modifiable biological markers, clinically relevant for further investigation in relation to potential future preventive strategies. Targeted prevention and treatment are becoming more prevalent in healthcare, and the results of this PhD thesis, if replicated, may be considered within this framework, notably in terms of reducing inflammation, especially for parents genetically predisposed to ADHD actively seeking to reduce the risk for their future children.
The research results from this PhD thesis prompt several important questions to be addressed in future research. This includes a more in-depth examination of how the timing, type, and overall “load” of inflammation/infection contribute as risk factors for psychiatric disorders and symptoms. Planned investigations include utilizing longitudinal data in the COPSAC2010 cohort on inflammation both before and after birth, incorporating other markers of inflammation, and using diary data from 0-3 years of age with information on fever, infections, sick days, and prescribed antibiotics filled out daily by parents. Additionally, the already collected MRI data will be used to examine the impact of inflammatory load and omega-3 faty acids on brain white and grey mater integrity at age 10. In terms of beneficial neurodevelopmental effects of fish oil supplementation, more research is needed, preferably larger RCT studies powered according to ADHD and ASD prevalences and with fish oil supplementation starting at an earlier timepoint.
