Abstract
BackgroundPrenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD). This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results.MethodsTo provide an orthogonal measure of fetal exposure, this study used meconium, the first stool of a newborn, to measure prenatal androgen exposure from infants in the Early Autism Risk Longitudinal Investigation (EARLI). EARLI is a familial-enriched risk cohort that enrolled pregnant mothers who already had a child with an ASD diagnosis. In the younger child, we investigated the association between meconium unconjugated (u) and total (t) concentrations of major androgens testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4), and ASD-related traits at 12 and 36 months of age. Traits were measured at 12 months with Autism Observation Scale for Infants (AOSI) and at 36 months with total score on the Social Responsiveness Scale (SRS). One hundred and seventy children had meconium and AOSI, 140 had meconium and SRS, and 137 had meconium and both AOSI and SRS.ResultsSeparate robust linear regressions between each of the log-transformed androgens and log-transformed SRS scores revealed three-way interaction between sex of the child, sex of the proband, and testosterone concentration. In the adjusted analyses, t-T, u-A4, and u-DHEA (P ≤ 0.01) were positively associated with AOSI scores, while u-T (P = 0.004) and u-DHEA (P = 0.007) were positively associated with SRS total score among females with female probands (n = 10). Additionally, higher concentrations of u-T (P = 0.01) and t-T (P = 0.01) predicted higher SRS total score in males with male probands (n = 63).LimitationsSince we explored three-way interactions, this resulted in a limited sample size for some analyses. This study was from an enriched-risk cohort which may limit generalizability, and this study used ASD-assessment scales as outcomes instead of diagnostic categories. Additionally, the novel use of meconium in this study limits the ability to compare the results in this cohort to others due to the paucity of research on meconium.ConclusionsThis study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies.
Highlights
Prenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD)
This study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies
Similar to the descriptive results presented by Park et al [18] but using a slightly different analytic sample due to availability of cord blood versus meconium samples, there were no sex differences in geometric mean of Autism Observation Scale for Infants (AOSI) score at 12 months: geometric mean (GM) = 5.4, geometric standard deviation (GSD) = 2.2 among males compared to GM = 4.9, GSD = 1.9 among females (P = 0.46)
Summary
Prenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD) This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results. Autism spectrum disorder (ASD) has an estimated prevalence of 1 in 59 among 8-year-old children in the USA [1,2,3] Within this population level estimate, there is a strong sex-dependent bias with a 4:1 male/female ratio, with some groups observing a closer to 2:1 male-tofemale ratio [4, 5]. The mechanism underlying this sex difference remains unknown but is of interest in understanding the etiology of ASD. Other studies using either amniotic fluid or cord blood reported mixed, but mostly null results [16,17,18,19]
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