**4. Conclusion**

Other factors related to intrauterine environment are maternal hypothyroxinemia [119], ma‐ ternal influenza [120], and high levels of sex hormone exposure related to infertility treat‐ ment [121].Thalidomide and anticonvulsant exposure in pregnancy is correlated to an increase in autism risk [122, 123]. Rasalam and his colleagues [124] showed that 8.9% of chil‐ dren exposed to sodium valproate in intrauterine life later develop autistic spectrum disor‐ ders such as autism or Asperger syndrome. Recently, Hadjikhani [125] have suggested that serotonin reuptake inhibitor use in pregnancy increases autism risk by causing hyperseroto‐

In many studies, the pre-perinatal complication rates in autistic disorder have been studied and a higher pregnancy-related complication rate has been demonstrated in autistic children [126, 127]. In a recent meta-analysis [128], the most strong risk factors for autism were ad‐ vanced maternal and paternal age, maternal gestational hemorrhage, gestational diabetes, ma‐ ternal prenatal drug use (particularly psychoactive drugs), and birth in a foreign country following immigration of mother. Both advanced maternal and paternal age are associated with autism. The underlying mechanism is unclear. Maternal age may be related to autism due to increased risk of chromosomal abnormalities in ova of increased age or because of unstable trinucleotide repeats [128]. The relationship between paternal age and autism is considered to result from imprinted genes (genes showing different expression patterns depending on the parent it originates), de novo spontaneous mutations that accumulate with advancing age in spermatagonia, or confounder effects of sociocultural environmental factors [129]. Another po‐ tential risk factor for autism is maternal birth abroad [130]. It has been suggested that this factor may result from absence of immunization that mother would develop against widespread in‐ fectious agents of the country in which she gives birth. Another possible explanation is about the potential role of maternal stress because of immigration [131]. A more detailed investiga‐ tion on the relationship between mother immigration and autism is needed. It has been demon‐ strated in some studies that gestational hemorrhage increases autism risk by causing fetal hypoxia [130]. Among other factors considered to cause hypoxia and associated with increased autism risk in some studies are fetal distress, maternal hypertension, prolonged labor, cord complications, low Apgar score, and cesarean section [132]. Gestational diabetes is another risk

Some studies demonstrated that prenatal stress increases autism risk [133, 134]. However, due to limitations that these studies are based on retrospective expressions of mothers and these mothers are generally susceptible for experiencing stressful life events outside preg‐ nancy period, these studies need to be supported by further studies. Spontaneous abortions, pre-perinatal complications, congenital anomalies, and neurologic/immunologic abnormali‐ ties are among the negative impacts of prenatal stress. Prenatal stress also has various nega‐ tive effects on brain development such as a delay in myelinization, an increase in sensitivity of amygdala to glucocorticoids, and abnormal development in dopaminergic system [135-137]. Autistic disorder is associated with a functional derangement in brain areas relat‐ ed to social cognitive functions in which amygdala and orbitofrontal cortex plays an impor‐ tant role. Orbitofrontal cortex is susceptible to effects of prenatal stress especially in the middle of gestation. Normal functioning of orbitofrontal cortex - amygdala axis is very im‐

ninemia and indirectly affecting amygdala and oxytocin levels.

328 Recent Advances in Autism Spectrum Disorders - Volume I

factor, with unknown biologic mechanism [128].

In line with studies aimed to understand the neurobiology of autism, the presence of altera‐ tions in regional brain anatomy and functional neuronal communicative network has been currently proved. The main role among factors underlying abnormal brain development be‐ longs to genetic factors. Evidence regarding that autism is a primarily genetic disorder is progressively increasing. Although environmental factors alone can explain a few cases, they are believed to increase autism risk by interacting with genetic susceptibility. Although data collected so far contribute to the ever-increasing body of knowledge about neurobiolo‐ gy of autism, they do not influence diagnosis and treatment of autism. Use of these data is aimed in future in differentiation of autism from other neurodevelopmental disorders and in diagnostic and therapeutic processes.
