In a prospective cohort study, researchers investigated the association between arachidonic acid–derived metabolites in umbilical cord blood and the development of autism spectrum disorder symptoms and adaptive functioning in children at age 6 years.

The study found that higher levels of arachidonic acid–derived dihydroxy eicosatrienoic acid in cord blood were significantly associated with increased autism spectrum disorder (ASD) symptom severity and impaired adaptive functioning, particularly in girls, suggesting prenatal exposure to specific lipid metabolites may influence autism risk and severity.

The study, published in Psychiatry and Clinical Neurosciences, included 200 mother-child pairs from the Hamamatsu Birth Cohort for Mothers and Children in Japan. The mean maternal age was 32.3 years (standard deviation [SD] = 5.0), and the gestational age at birth was 39.1 weeks (SD = 1.2). Cord blood samples were collected at birth and analyzed using liquid chromatography-mass spectrometry to quantify arachidonic acid (AA)-derived epoxy eicosatrienoic acid (EET) and dihydroxy eicosatrienoic acid (diHETrE) metabolites. The mean concentrations of total epoxy octadecenoic acid, diHOME, EET, and diHETrE in cord blood were 1,075.2 pg/mL (SD = 720.1), 1,303.9 pg/mL (SD = 464.4), 518.3 pg/mL (SD = 464.5), and 3,445.7 pg/mL (SD = 955.2), respectively.

At age 6 years, children were assessed for ASD symptoms using the Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2) and for adaptive functioning using the Vineland Adaptive Behavior Scales, 2nd Edition (VABS-II). 

The prevalence of ASD symptoms based on ADOS-2 calibrated severity score (CSS) in the cohort was:

• 49% had minimal-to-no symptoms (CSS = 1-2)
• 14.5% had mild symptoms (CSS = 3-4)
• 19.5% had moderate symptoms (CSS = 5-7)
• 17% had severe symptoms (CSS = 8-10).

Results showed that higher levels of total diHETrE, 11,12-diHETrE, and 14,15-diHETrE in cord blood were significantly associated with increased ASD symptom severity based on ADOS-2 CSSs, after adjusting for confounders. Specifically, high 11,12-diHETrE levels were associated with greater impairment in the social affect domain, while low 8,9-diHETrE levels were associated with more repetitive/restrictive behaviors.

The findings indicated that girls might be more vulnerable to the autism-related effects of prenatal lipid metabolites, as female study participants showed significant associations for 8,9-diHETrE, 11,12-diHETrE, and total diHETrE. Furthermore, higher 11,12-diHETrE levels correlated with lower scores in the socialization domain of the VABS-II, particularly in coping skills, indicating that autism symptoms and adaptive skills in children may be tied to umbilical cord blood markers.

No significant associations were found between ASD symptoms or adaptive functioning and EET levels or EET/diHETrE ratios, which reflect soluble epoxide hydrolase activity.

The researchers proposed that altered levels of proinflammatory diHETrE metabolites during the fetal period might influence neurodevelopment and contribute to the pathogenesis of ASD, possibly through maternal immune activation. They suggested that the dynamics of AA-derived diols might be important in shaping the developmental trajectory of children after birth.

Strengths of the study included its prospective design, the use of standard diagnostic tools, and the inclusion of a relatively large sample with an equal sex ratio; limitations included the lack of generalizability to other populations and the absence of longitudinal data on AA metabolite levels beyond the neonatal period.

The findings shed light on the potential role of lipid metabolites in the pathophysiology of ASD and highlighted the importance of the prenatal environment in shaping neurodevelopmental outcomes.

The disclosure statement is available in the study.