Can CMV infection lead to ASD?

Recent study points that CNS abnormalities may play a role in development of ASD in children with cCMV

Cytomegalovirus (CMV) belongs to herpes viridae family and is the largest member. Humans are the reservoir of CMV. It can be transmitted from one person to another via body fluids like saliva, urine, breastmilk, semen and blood. CMV infection could be primary or non-primary (latent). Primary infection of host is when previously uninfected human gets infected for the first time. And non-primary infection also known as latent infection is reactivation of the previous infection or infection with different strain of virus.¹ Primary infection is associated with higher risk of transplacental transmission² (30-35%) than non-primary infection³ (1.1- 1.7%).

The foremost risk factor which leads to primary CMV infection during pregnancy is exposure to children for long period of time as they can shed virus in urine and saliva up to 24 months. The shedding of virus in cervicovaginal secretions and urine increases as the pregnancy advances therefore increasing the chances of transmission to fetus during the last trimester⁴ (58 – 78%).

Congenital CMV (cCMV) infection is one of the most common intrauterine infection seen worldwide. It is also on the most common non-genetic cause for sensorineural hearing loss.⁵ In India about 1.2% children are affected by CMV and about 90% are asymptomatic. The clinical manifestation spectrum of cCMV infection is wide and can vary from being asymptomatic to having neurodevelopmental delay and death. Asymptomatic infection is not entirely benign and can lead to long term morbidities in about 10 – 15 % of the infected children. Primary infection has initial manifestations like fever, malaise, headache, lymphadenopathy, rash, hepatosplenomegaly and arthralgia. Fetal abnormalities associated with CMV infection are microcephaly, ventriculomegaly, lenticulostriate vasculopathy, intrauterine growth restriction, hepatomegaly, intracranial calcifications, pericardial effusion and ascites. Hearing loss is hallmark of cCMV and can present at birth or later in life, therefore regular hearing assessment should be done.

Recently many small studies have reported a possible connection between cCMV and autism spectrum disorder (ASD). A large study done on about 3 million children with cCMV, deduced that children with cCMV are more prone to be diagnosed with ASD by age 4 – 7 years than in children who don’t have cCMV infection. However, when analysis was confined to children with cCMV infection without CNS abnormalities the results obtained were not statistically significant. This suggests that CNS abnormalities may play a role in development of ASD in children with cCMV, emphasizing on the need of neurodevelopmental surveillance in all children with cCMV.⁶

Although there is no definitive treatment for congenital or acquired CMV, it is better to screen for CMV infection in neonates with symptoms or asymptomatic neonates with subtle manifestations. Timely initiation of ganciclovir or valganciclovir can prevent further progression of deafness and neurodevelopment delay. Hence although not implemented but universal screening of CMV pregnancy should be done to prevent morbidity and mortality.

References:

1. Revello MG, Gerna G. Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin Microbiol Rev. 2002 Oct;15(4):680-715.
2. Picone O, Vauloup-Fellous C, Cordier AG, Guitton S, Senat MV, Fuchs F, Ayoubi JM, Grangeot Keros L, Benachi A. A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome. Prenat Diagn. 2013 Aug;33(8):751-8.
3. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007 Jul-Aug;17(4):253-76.
4. Bodéus M, Kabamba-Mukadi B, Zech F, Hubinont C, Bernard P, Goubau P. Human cytomegalovirus in utero transmission: follow-up of 524 maternal seroconversions. J Clin Virol. 2010 Feb;47(2):201-2.
5. Lazzarotto T, Guerra B, Gabrielli L, Lanari M, Landini MP. Update on the prevention, diagnosis and management of cytomegalovirus infection during pregnancy. Clin Microbiol Infect. 2011 Sep;17(9):1285-93.
6. Pesch MH, Leung J, Lanzieri TM, Tinker SC, Rose CE, Danielson ML, Yeargin-Allsopp M, Grosse SD. Autism Spectrum Disorder Diagnoses and Congenital Cytomegalovirus. Pediatrics. 2024 Jun 1;153(6):e2023064081. doi: 10.1542/peds.2023-064081. PMID: 38808409; PMCID: PMC11153325