2021 Lærke Sass – MD

Increasing evidence has linked n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) and vitamin D with normal brain development. The intake of n-3 LCPUFA is generally decreasing in western populations, and vitamin D deficiency is considered a major global health problem that is highly prevalent among pregnant women. Since fetal and newborn vitamin D status is almost entirely dependent on vitamin D from the mother, an adequate maternal level is crucial. Likewise, fetal brain development relies on sufficient maternal dietary intake of n-3 LCPUFA.

During the brain growth spurt from the second half of pregnancy through the first 2 years of life, n-3 LCPUFA is accumulated in the central nervous system, affecting brain structure, function, and metabolism. Likewise, in animal models, vitamin D is associated with altered brain structure and behavior, and observational studies have linked prenatal vitamin D deficiency to several neurodevelopmental and psychiatric diseases such as Attention Deficit Hyperactivity Disorder (ADHD), autism spectrum disorders, and schizophrenia.

A generally accepted hypothesis is that the perinatal period is a window of vulnerability where the child is particularly susceptible to exposures affecting their health throughout life and their risk of developing diseases.

The underlying hypothesis of this thesis was that maternal supplementation with the essential nutrients n-3 LCPUFA and vitamin D during pregnancy would enhance the offspring’s neurodevelopment. Hence, this PhD thesis aimed to investigate the effect of supplementation with either fish oil consisting of n-3 LCPUFA and high-dose vitamin D given to expectant mothers during the third trimester of pregnancy on offspring neurodevelopment from birth to 6 years of age.

The thesis consists of two papers based on data from the unselected mother-child cohort, Copenhagen Prospective Studies on Asthma in Childhood, COPSAC2010, comprising 738 women and their children. The pregnant women participated in two double-blinded, factorial designed randomized controlled trials (RCTs) of either n-3 LCPUFA, high-dose vitamin D, or matching placebo given from week 24 in pregnancy to one week after birth.

The children were followed from birth at 12 pre-scheduled clinical visits. Their neurodevelopment was evaluated at several timepoints covering various domains. Age of motor milestone achievement was prospectively registered in a registration form based on the Denver Developmental Index and the WHO milestone registration. At 1 and 2 years, early language development was estimated with the MacArthur-Bates Communicative Development Inventories, and cognitive development wasii assessed with the Bayley Scales of Infant and Toddler Development at 2.5 years. The general neurodevelopment was evaluated with the Ages & Stages Questionnaire at 3 years, and the emotional and behavioral problems at 6 years were assessed with the Strengths and Difficulties Questionnaire.

Paper I evaluates the neurodevelopment of children born to mothers participating in a double-blind RCT of n-3 LCPUFA supplementation or matching placebo. We found that children born to mothers who received n-3 LCPUFA during pregnancy had an increased word production at 1 year and a reduced impact of emotional and behavioral problems at 6 years. Additionally, boys in the n-3 LCPUFA supplemented group achieved gross motor milestones earlier, had a higher cognitive score at 2.5 years and a reduced impact of emotional and behavioral problems at 6 years.

In Paper II we analyzed the effect of maternal high-dose vitamin D pregnancy supplementation on offspring neurodevelopment. The study is the first double-blind RCT, which compares the effect of high-dose versus standard dose of vitamin D supplementation during the third trimester of pregnancy.

Overall, we observed no effect of the high-dose vitamin D on the children‘s achievement of motor milestones, cognitive development, general neurodevelopment, or emotional and behavioral problems. There was no effect on language development at 1 year, while the finding of an isolated negative effect on word production at 2 years was present for the children in the high-dose vitamin D group.

Collectively, these findings contribute with important knowledge of the effects of maternal supplementation with n-3 LCPUFA and vitamin D in pregnancy on offspring neurodevelopment. Overall, there was no effect of the high-dose vitamin D supplementation on the children’s neurodevelopment, whereas n-3 LCPUFA supplementation improved the neurodevelopment at several time points using various assessment methods, supporting the theory of a window of vulnerability. In the future, a recommendation of fish oil supplements should be considered as a possible strategy to improve healthy brain development.