On the Spectrum

A Prospective Study of Fetal Head Growth in Children, Autistic Traits and Autism Spectrum Disorder
DISCUSSION
In a study based on two large prenatal cohorts, we found that children with slower fetal HC
growth rates had more autistic traits as measured postnatally. However, these findings were
not replicated when we examined children with a clinical diagnosis of ASD.
Our finding of slower HC growth in children with autistic traits is consistent with
several small studies reporting slightly smaller HC at birth in children later diagnosed with
ASD (Courchesne, Carper and Akshoomoff 2003; Courchesne, Pierce, Schumann, Redcay,
Buckwalter et al. 2007). Slower head growth prenatally may reflect aberrant early brain
development consistent with later findings in childhood ASD that include altered morphology
of gray and white matter, as well as aberrant connectivity (Parellada, Penzol, Pina, Moreno,
Gonzalez-Vioque et al. 2014). Of note, a postmortem study of children with ASD showed
local disorganization across different cortical layers suggestive of aberrant prenatal neuronal
migration (Stoner, Chow, Boyle, Sunkin, Mouton et al. 2014).
Several biological mechanisms could underlie the association of prenatal HC growth
with autistic traits. Environmental factors, such as maternal thyroid dysfunction or vitamin
D deficiency may lead to autism-like symptoms through restriction of prenatal brain growth
(Roman et al. 2013; Whitehouse, Holt, Serralha, Holt, Hart et al. 2013; Korevaar, Muetzel,
Medici, Chaker, Jaddoe et al. 2016). Alternatively, autistic traits and prenatal HC growth may
share a similar genetic background. Interestingly, evidence from histopathological studies
showed high expression of ASD candidate genes in the fetal cortex, although the role of
these genes in prenatal brain growth has not been established yet (Willsey, Sanders, Li, Dong,
Tebbenkamp et al. 2013; Birnbaum, Jaffe, Hyde, Kleinman and Weinberger 2014).
Future studies should clarify whether our finding of a relation between prenatal head
growth and autistic traits is indicative of a neurobiological pathway of ASD, or may reflect
features of developmental delay not necessarily specific to ASD.
Considering the finding of an association between slower HC growth prenatally and
increased autistic traits postnatally, we hypothesized that those children with an ASD
diagnosis would also show an altered (slower) HC growth trajectory. As we did not detect
such differences, our results do not fully support a continuum in the neurobiology of ASD in
the context of HC, which would imply similar differences at the severe end. Such a continuum
was hypothesized based on evidence across genetic (Colvert, Tick, McEwen, Stewart, Curran
et al. 2015), phenotypic (Constantino et al. 2003) and neuro-imaging studies (Blanken, Mous,
Ghassabian, Muetzel, Schoemaker et al. 2015). However, autistic traits and ASD affect the
brain at many levels. Some brain differences related to ASD may form a dose-response-type
relation with autistic traits, such that the most severely affected patients have the most
marked differences, while other characteristics may not exhibit such associations. There are
several alternative explanations for the absence of this finding. While this was the largest
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