Prenatal Polyunsaturated Fatty Acid Levels in Association with Autism Spectrum Disorder

Background: Polyunsaturated fatty acids (PUFAs) are critical to neurodevelopment. Though emerging work has identified associations between certain prenatal nutrients and reported supplements in association with autism spectrum disorder (ASD), and suggested altered levels of PUFAs in individuals already diagnosed with ASD, no prior study has examined the association between measured levels of prenatal PUFAs and ASD in order to determine potential etiologic involvement of these fats.

Objectives: To determine whether levels of PUFAs, measured in stored mid-pregnancy serum samples, differ in mothers who go on to have a child with ASD as compared to those who have an unaffected child.

Methods: This population-based statewide case-control study includes approximately 500 cases and 500 general population (GP) controls, matched on sex and month and year of birth (2011-2013). Cases of ASD were identified from the California Department of Developmental Services (DDS), and GP controls were randomly selected within strata of matching factors from birth certificate files after excluding DDS clients. Prenatal serum samples were drawn from the California Biobank Program, and levels of specific omega 3 and omega 6 PUFAs were measured using liquid chromatography-mass spectrometry/high resolution mass spectrometry (LC-MS/HRMS). Conditional logistic regression analyses, accounting for matching factors and adjusted for potential confounders, were used to examine the association between PUFAs (as individual fatty acids and as classes) and ASD.

Results: In preliminary analyses, mean levels of PUFAs did not significantly differ. In adjusted analyses examining associations with extremes of the distribution, there was a suggestion of an increase in odds of ASD for individuals in the lowest 5^th percentile of linoleic acid levels (OR=1.57, 95% CI 0.90-2.76), relative to those with mid-distribution levels. Reductions of approximately 20% in odds of ASD for those in the highest 5^th percentile of total PUFAs and total omega 6, were also observed, though these associations also did not reach statistical significance (OR=0.83, 95% CI 0.44, 1.56, respectively). Analyses will be updated as final samples are processed. Additional analyses will also investigate potential non-linear relationships between these fats and ASD using cubic splines, as well as associations with PUFAs measured in neonatal bloodspots in a subset of 400 cases and controls. Secondary analyses will examine the odds of ASD with and without comorbid intellectual disability (ID), relative to GP controls.

Conclusions: Preliminary findings from this large population-based case control study did not reveal significant associations between prenatal PUFA levels and ASD. However, associations similar in direction and magnitude for extremes of total PUFA, as well as linoleic acid specifically, are generally consistent with our previous results based on reported maternal diet, suggesting potential influences of very high and very low levels of these fats. Given the critical role of PUFAs in fetal brain development, and their influence on mechanisms with evidence for involvement in ASD etiology (inflammation and oxidative stress), further exploration of these potential associations is needed. Findings here will be updated using the full study group, exploring more complex exposure distribution relationships, and considering additional outcome subtypes.