Abstract
Objectives
Previous studies have consistently reported on the association between maternal metabolic conditions, like obesity and diabetes, and a higher risk of offspring ASD. However, the underlying mechanisms remain elusive. Branched-chain amino acids (BCAAs) are known to be involved in the inflammatory pathways underpinning obesity and diabetes, and studies have also shown associations between BCAAs and ASD. We sought to examine the joint associations of maternal metabolic conditions and maternal plasma BCAAs with offspring risk of ASD and explore whether the associations differ by child sex.
Methods
This study was comprised of 864 mother-child pairs, a subset of the Boston Birth Cohort (BBC). Maternal plasma BCAAs were measured by liquid chromatography-tandem mass spectrometry (LC-MS) in samples collected 24–72 hours postpartum. A composite BCAA score was created using principal components, and obesity and diabetes (ob/DM) were combined into one variable (none vs any). Logistic regression was used to explore the role of BCAAs as risk factors, mediators, or effect modifiers, along with maternal ob/DM and other covariables. BCAA, ob/DM, and sex interactions were also examined.
Results
Maternal plasma BCAAs alone were not associated with child ASD and did not mediate the path between maternal ob/DM and ASD. However, in the presence of maternal ob/DM, maternal BCAA score was significantly associated with ASD (adjusted OR 2.35, 95% CI 1.21 – 4.55). Maternal BCAA score was also significantly associated with ASD in males compared to females (adjusted OR 4.91, 95% CI 2.48 – 9.69). There were significant interactions of leucine and valine with ob/DM and of leucine and isoleucine with male sex on the risk of offspring ASD. Finally, compared to females without maternal metabolic risk factors, males with both maternal ob/DM and high maternal BCAA score had over eight times higher risk of ASD.
Conclusions
While male sex and maternal ob/DM were known risk factors of child ASD, our study showed that elevated levels of maternal plasma BCAAs further increased the risk of ASD under these conditions. Additional studies are warranted to clarify the role of BCAAs in ASD; if confirmed, BCAAs have potential as early biomarkers of future risk of ASD, especially in the presence of maternal metabolic disorders and/or a male fetus.
Funding Sources
Health Resources and Services Administration grant.
Supporting Tables, Images and/or Graphs
Cord blood metabolites linked with an ADHD diagnosis in childhood
