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The Relationship between Premature Birth, Autism, and Stages of Brain Development

Although it’s well known that neurogenesis or the production of new neurons occurs throughout the lifespan, there are only a few select areas of the brain that continue to do so. Examples include the subventricular zone underlying the neocortex that supplies new neurons for the olfactory bulb, as well as the dentate gyrus of the hippocampus, a structure associated with memory.

In the prenatal period, however, neurons supplying the neocortex are produced up to 29 weeks of gestation in humans [1]. (Pregnancy lasts approximately 40 weeks.) Malik et al. (2013) have found that the hypoxic (low oxygen) environment of the womb is vital for the continued proper development of the brain. Not only did they find that neuron production was reduced in preterm infants, but they also found that in an animal model of preterm delivery, normal neurogenesis could be partly resumed by the application of an hypoxic mimic, dimethyloxallyl glycine.

Stages of neurogenesis in the cerebral cortex. Borrowed from here.

Premature birth is a considerable risk factor for a variety of neurodevelopmental conditions, including autism. For example, Limperopoulos et al. (2008) reported that 26% of the preemies in their study displayed measurable symptoms of  autism in infancy, although it’s unknown how many of these infants would have gone on to receive an autism diagnosis in childhood as this was not a longitudinal study. However, they did find that younger gestational age was an important factor in increased risk for positive scores on the Child Behavior Checklist and Vineland Scales.

Another study which used the M-CHAT in toddlers to assess autism symptomology found that the presence of other disabilities in the extreme preterm population (<26 weeks gestation) could lead to diagnostic confusion. In fact, large percentages of those with severe motor, cognitive, hearing, or vision impairments screened positive on the M-CHAT, prompting the authors to advise caution in applying the autism label to this population without more thorough testing [2]. However, another study by Johnson et al. (2010) found that extreme prematurity was indeed a risk factor for autism, with 8% of their sample eventually receiving an autism spectrum diagnosis by later childhood. Thus, this last study is probably a better estimate of true autism risk in extreme preterm children. But it’s also apparent that these preterm kids are at high risk for a variety of neurodevelopmental and medical conditions.

One of the more interesting points to note, however, is that extreme preterm delivery overlaps the period in which neurogenesis is still occurring in the developing brain, suggesting that disturbances to the production of neurons may play an important role in autism risk. In support of this, premature birth often coincides with an increased risk for haemorrhage (bleeding) within the germinal zone (neural stem cells). Del Bigio (2011) reports that haemorrhage in preterm infants is accompanied by decreased neuronal proliferation.

However, from our own recent work, we know that genes involved in autism are likely to influence multiple stages of a neuron’s development. Therefore, it is quite reasonable to suspect that not only is neurogenesis perturbed in extreme prematurity, but maturation of already-born neurons is probably also affected. How this ultimately leads to autism in only a subset of cases is still a partial mystery. Hopefully future research will allow us to better understand when, why, and how autism occurs and specifically what prematurity does to tip that balance.

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