We define ASD as 

A disorder characterized by impaired social interaction and language skills and restricted/repetitive behavior in the toddler period and later in life. It is congenital disease disrupting a child’s neurological development. It begins as a maternal-to-fetal infection causing aberrant immune activation and is transmitted to a child in the prenatal period, continues throughout the postnatal period causing somatic genetic changes and atypical brain development.

1. ASD is a Congenital Disorder Resulted from Infectious-Inflammatory Event in utero

According to the CDC, “the critical period for developing ASD occurs before, during, and immediately after birth”. Nowadays, there are several theories regarding the etiology of ASD, but most of them are linked to the pregnancy period, indicating that the main processes affecting the autistic phenotype occur prenatally.

In a study, in which all children born in Denmark from 1980 to 2005 were included, it was found that admission to a hospital due to maternal viral infection in the first trimester and maternal bacterial infection in the second trimester was associated with the diagnosis of ASD in the offspring. The diagnosis of ASD in the children studied was determined through nationwide registers.

 

In a similar Swedish study published in 2019, with 1.8 million children participating, it was confirmed that any viral infection during pregnancy significantly increases the risk of ASD in a child. These results support the hypothesis that early prenatal viral infection increases the risk of ASD and it shows the possible role of bacterial infections in the prenatal period as well.

 

These findings were confirmed in a murine study. Pregnant mice were injected with poly-I:C, a substance inducing the immune reaction as it would be during viral infection. Poly-I:C injections significantly increased the rate of autism in the offspring, confirming the role of infection during pregnancy and following maternal immune reaction in the ASD development.

 

As well, several studies show that both behavioral and clinical signs and symptoms of ASD are manifested in the first months of an infant’s life, thus rejecting the common opinion that ASD is a disorder developed by age 3.

 

Moreover, some of the brain alterations commonly observed in ASD children can only be initiated during prenatal brain development. For instance, ASD children have a decreased number of Purkinje cells (PCs) with the absence of empty baskets. PCs are only developed in the prenatal period, meaning that this alteration could take place only before birth.

The figure to the right shows the processes occurring in utero that lead to ASD.  

A mother infected with some viral/bacterial infection (or an existing chronic infection is reactivated), results in maternal immune activation, i.e. her immune system starts producing inflammatory cytokines, reactive oxygen species, etc. to fight the infection. This form an inflammatory background that may last from several days to the whole pregnancy.

Infectious agents, cytokines and other inflammatory species cross the placenta and are transmitted to the fetus. In a weak fetus, infection and inflammatory species may cause DNA alterations both directly and via oxidative stress.

Altered genes result in atypical brain formation, that later will result in autistic symptoms in a child.

When the child is born, initially the symptoms are not fully pronounced. Parents may notice that the child is too quiet or vice versa, very irritable, while the main symptoms of autism are not manifested. We suggest that this is a result of the protection by maternal antibodies that usually lasts for the first 12 months after birth.

After this period, when the child begins to rely on own immune system, the infection reactivates, worsening the condition and leading to noticeable regression - a common pattern for the children with autism. 

In some cases, it is not necessarily reactivation of infection that occurs first. It can be surgery, physical or psychological trauma, vaccination - any event that triggers the immune system. 

However, it is important to understand that these factors do not cause autism, but rather trigger the revealing of the congenital condition. Eventually, with or without the trigger, noticeable regression of symptoms would occur. 

The figure to the right shows the processes occurring in a child with ASD.  

Infection, inflammation, immune alterations, DNA damage, and abnormal brain development are key factors to consider in autism. Starting from infection, the chain of interconnected events is triggered leading to the manifestation of the symptoms of autism. 

These factors negatively affect each other constantly, which gives no room for recovery as each factor perpetuates the next.

For instance, Infection causes inflammation, which in turn alters the neurohormones levels. These hormones negatively affect the immune system functioning, which leads to occurrent infection reactivation, and thus the cycle repeats over and over again.

 

Thus, the treatment should focus on disrupting the links of this vicious circle: inhibition of infection, recovery of the immune system, decrease of inflammation, and restoration of the gastrointestinal tract.

Affecting these factors eventually will result in normalization of the genes expression and consequently in normal brain functioning.

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