Autism spectrum disorder (ASD) is a neurological and developmental disorder that generally appears before the age of 3 but can be diagnosed at any age. It is more often in boys than girls and the prevalence is not affected by race. It impacts the normal development of the brain and affects the social interaction, communication skills and cognitive function [1].

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), individuals with ASD often have difficulties in verbal and non-verbal communication, social interactions, restricted interests, repetitive behaviors, symptoms that affect their ability to function in diverses areas of life. Its important to know that some children who have been diagnosed with autism develop normally during early childhood and may acquire functional language. However, there is a gradual loss of language [2].

Therefore, the American Academy of Pediatrics recommends that all children be screened for developmental delays and disabilities during regular doctor visits at 9, 18 and 24 or 30 months. The earlier ASD is diagnosed, the sooner treatments and services can begin [1]. The increase in ASD diagnoses has been growing exponentially in recent years [3].

In 2020, in the United States, the Centers for Disease Control and Prevention (CDC) recorded one case of autism for every 36 children [4].

Although there are no definitive answers that justify this increase, some factors may be related such as: increased public awareness of the topic, professional training and ease of diagnosis, access to new information, etc. One of the proposed reasons for autism is viral infection Congenital Cytomegalovirus (cCMV) in the early stages of development. The mechanism by which viral infection could lead to autism is still unclear. However, the etiology of ASD have been exploring for current studies while ignoring the additive effects of other factors [2-4].

More than 40 years ago, CMV infection was related to ASD, as revealed by researchers. However, these studies still reveal new information. According to the new study, children with cCMV were more likely to have ASD diagnoses [5].

CMV is a type of herpesvirus (herpesvirus type 5). Infection caused by cytomegalovirus is very common, its transmission occurs through sexual and non-sexual contact, through body secretions. After infection, the virus persists in leukocytes and tissue cells with intermittent shedding in urine, saliva, and genital secretions. Vertical transmission most commonly occurs in utero, but infection can be acquired at the time of birth or via human milk [3].

The majority of those infected are asymptomatic and do not develop serious conditions. Blood tests show that between 50% and 90% of adults have contracted a CMV infection at some point in their lives. In general, no treatment is needed, but if the infection is severe, antiviral medications may be used [6 ].

Newborns diagnosed with CMV may present with cognitive changes, liver, spleen, lungs, and growth changes. Hearing loss is the main sequelae that can be detected soon after birth or can develop later in childhood. Exposure to the CMV virus during the first trimester of pregnancy increases the risk of ASD [7].

Nowadays, it is believed that CMV is one of the etiological agents of ASD and leads to apoptosis in infected cells because it may interfere with the induction of neural differentiation. Neurological symptoms (such as hearing impairment, epilepsy, motor and cognitive impairments, visual problems and cerebral) may be related to development after disease [8].

Among 37 ASD patients, 89.2% occurred in CMV seropositive patients, and 10.8% occurred in the seronegative group. Therefore, it can be demonstrated that CMV seroprevalence is a risk factor for patients with ASD. The biggest challenge is most healthy people who are infected with CMV are asymptomatic. Furthermore, like other members of the Herpesvirus family, CMV establishes latent infection, that is, it remains dormant within cells, even after the acute infection has resolved. Therefore, periods of viral reactivation may occur, especially in immunocompromised individuals [5]. Therefore, studies have demonstrated a relationship between congenital cytomegalovirus infection and the onset of ASD. However, the mechanism of action of the virus in the body for the development of such pathology is still uncertain [5].

The immune response to the virus may be related, but further studies are needed to clarify how the system affects the embryo or fetus, causing the characteristic symptoms of ASD. Most studies linking ASD and CMV are focused on congenital infection because this period is critical for neurodevelopment and susceptible to be damaged by CMV infection. However, most postnatal infection with serological evidence of CMV IgG occur within 1 year of age and also poses imminent risks to brain development and should not be neglected. Furthermore, the majority of postnatal infections are asymptomatic and the 15% of children with cCMV infection develop sensorineural hearing loss by age 5 years [5].

The first year of life is also a critical period for brain development, when more neurons continue to migrate to the outermost layer of the cortex, thereby significantly increasing cortical gray matter volume [9,10].

However, the limitations found in the studies are numerous. The CMV IgG reflects whether the patient was infected and does not determine when the infection occurred. This diagnostic test is performed retrospectively using serum antibodies [11,12].

The biggest challenge is screening in the prenatal period to avoid congenital and postnatal viral transmission. Universal cCMV screening programs that provide an opportunity for early intervention need to be implemented [7]. The challenges for routine prenatal screening are many. Although serological screening for primary maternal CMV infection is reliable, it is not possible to diagnose non-primary infection using maternal serology. That is, once the maternal infection is non-primary, it is not amenable to serological diagnosis, since the available screening test does not identify the exact moment of infection and, therefore, it is not possible to prevent fetal transmission to the children of mothers who have previously been infected. Therefore, routine prenatal screening is not yet recommended outside the research setting. However, women who have primary infection would benefit from screening, especially because the risk of congenital infection increases in the first trimester and screening would prevent possible sequelae of the disease. However, although it may seem simple, it is not possible to predict infection, since the window between detection of maternal CMV viremia and positive serology (IgM and then IgG) occurs from 1 to 2 weeks. This means that placental/fetal infection may already have occurred when serology is positive and represents a great challenge [7].

In recent years, it has been identified that significant neonatal sequelae occur only after infection in the first trimester, so screening would be essential in this postnatal period. It is known that maternal treatment with valacyclovir can significantly reduce the risk of congenital CMV and neurological sequelae, which increases the possibilities of new screening methods being identified in the near future [7]. CMV PCR testing on urine or saliva swabs within 3 weeks of birth is essential to identify disease in the postnatal period. In symptomatic neonates with confirmed congenital infection, postnatal treatment with valganciclovir/ganciclovir should be considered and initiated within the first 4 weeks of life [7].