The role of vitamin D and Omega-3 long chain polyunsaturated fatty acids in children with Autism Spectrum Disorder : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science, Massey University, Albany, New Zealand

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Background: The efficacy of vitamin D and omega-3 long chain polyunsaturated fatty acid (omega-3 LCPUFA), each individually, in Autism Spectrum Disorder (ASD) has been tested in a few trials and the results are inconclusive. Furthermore, several observational studies have observed low vitamin D and omega-3 LCPUFA status in populations with ASD. Children with ASD are susceptible to nutritional issues and poor diet quality due to sensory, behavioural and gastrointestinal issues associated with the condition, though no information regarding these children’s nutritional status is available in New Zealand. Also, no validated nutritional quality assessment tools are available for this population. Aim and Objectives: The overall aim of this study was to investigate the role of vitamin D (VID), omega-3 LCPUFA (OM), or both (VIDOM) in ASD in children through systematically reviewing literature and conducting an intervention trial with these nutrients. The primary objective was to investigate the efficacy of vitamin D, omega-3 LCPUFA, both on core symptoms and sensory issues after correcting major nutritional deficiencies and secondary objectives were to investigate the efficacy of intervention on irritability and hyperactivity, to study dietary adequacy/nutritional status of children with ASD, and to validate a Dietary Index of Children’s Eating (DICE) questionnaire against 4-day estimated food record (4DFR). Methods/Design: New Zealand children with ASD (age 2.5-8.0 years) participated in a 12- month randomised, double-blind, placebo-controlled, 2x2 factorial trial. Prior to trial entry, children’s dietary adequacy and nutritional status were assessed by 4DFR, DICE questionnaire (designed based on New Zealand Ministry of Health Food and Nutrition guidelines), and nutritional biomarkers (25(OH)D, red blood cell fatty acids, iron, calcium, albumin, vitamin B12, and folate). Data regarding dietary supplement use and special/exclusion diet, demographics and anthropometrics (height and weight) were also collected. Children then were randomly assigned to one of four treatment groups; daily 2000IU vitamin D3, 722 mg docosahexaenoic acid (DHA), both supplements, or placebo, and behaviours were assessed. Core symptoms were assessed using Social Responsiveness Scale (SRS), sensory issues using Sensory Processing Measure (SPM), problem behaviours including irritability and hyperactivity using Aberrant Behaviour Checklist (ABC). Outcome measures were analysed pre- and post-intervention. Pair-wise mixed effects longitudinal models were used for data analysis. Results: 309 families registered their interest in the study, of whom 190 families were either excluded or not enrolled. The children of remaining families (n=119) were screened for nutritional deficiencies and high serum 25(OH)D concentrations, of whom two children were excluded. Overall, 62% (73/117) of children completed the trial (placebo 16, VID 19, OM 23, VIDOM 15). The mean serum 25(OH)D concentrations (nmol/L) increased in the VID (27±14, P<0.001) and VIDOM (36±17, P<0.001) groups and changed slightly in the OM (1.1±14, P>0.05) and placebo (8.9±23, P>0.05) groups. The median omega-3 index (%) increased in the OM [4.4 (3.3, 5.9), P<0.001] and VIDOM [4.0 (2.0, 6.0), P<0.001] groups and decreased in the VID [-0.2 (-1.0, 0.1)] and placebo [-0.5 (-0.9, -0.1), P>0.05] groups. Compared to placebo, a greater improvement in multiple outcomes in the intervention groups was observed: SRS-social awareness for OM (0.4±2.9 vs. -1.4±2.3, P=0.03) and VIDOM (0.4±2.9 vs. -1.7±3.5, P=0.03); SRS-social communicative functioning for VIDOM (-5.6±10 vs. -16±24, P=0.07); SRS-total for OM (-5.8±12 vs. -17±18, P=0.08); SPM-taste and smell for VIDOM (-0.3±1.7 vs. -2.5±4.3, P=0.06), SPM-balance and motion for OM (-0.1±4.7 vs. -2.6±4.3, P=0.09), ABC-irritability for VID (0.8±6.1 vs. -4.0±4.9 P=0.01) and OM (0.8±6.1 vs. -5.0±5.0, P=0.001); and ABChyperactivity for VID (-0.8±5.6 vs. -5.2±6.3, P=0.047). Out of 86 children whose food records were available, approximately 50% (39/86) reported taking dietary supplements and 15% (13/86) were on a special/exclusion diet. A large proportion of children had dietary intake for vitamin D below the Adequate Intake (AI, 96%), protein below the Average Macronutrient Distribution Range (AMDR, 65%), and iodine below the Estimated Average Requirement (EAR, 54%). Dietary intake of fibre (43%) and vitamin E (37%) was also below the AI by at least one third of children. All or most children exceeded the recommendations for sodium (100%), total saturated fat (80%) and sugar (52%). There was a significant and positive correlation (r=0.7; P<0.001) and good agreement (ĸ=0.6) between total scores from DICE (64±16) and 4DFR (58±11). Participants in the highest tertile of DICE had higher intakes of magnesium (P=0.02), vitamin A (P=0.03) and fibre (P=0.06). Conclusions: Vitamin D and omega-3 LCPUFA, each individually or together, improved some behavioural symptoms of ASD. However, large attrition rates and resultant loss of statistical power preclude definitive conclusion and warrant further trials. Also, the baseline assessment of nutrition confirms nutritional issues and poor diet quality in children with ASD. Given the importance of nutrition in growth and development and in the management of ASD, screening of the nutritional status of children with ASD for nutrient adequacy to reduce under- or over-consumption of nutrients is recommended. DICE is a valid tool for the assessment of diet quality in children with ASD living in New Zealand.
Autism spectrum disorders in children, Nutritional aspects, Autism in children, Diet therapy, Autistic children, Nutrition, Vitamin D in human nutrition, Fatty acids in human nutrition, Omega-3 fatty acids, Therapeutic use