Maternal cytomegalovirus infection in the first trimester of pregnancy: timing, fetal brain injury, and long-term neurodevelopmental outcomes including autism spectrum disorder.

Abstract

Congenital cytomegalovirus infection is the leading nongenetic cause of sensorineural hearing loss and is associated with a broad spectrum of neurodevelopmental outcomes. A possible association between congenital cytomegalovirus and autism spectrum disorder has been hypothesized for several decades, based on case reports and small retrospective studies. The objective was to estimate the strength of the association between congenital cytomegalovirus and neurodevelopmental abnormalities including autism spectrum disorder, their dependence on the timing of maternal infection, and their potential neuroanatomical correlates. We conducted a prospective observational cohort study including children with confirmed congenital cytomegalovirus infection followed at a single tertiary referral center in France between 2001 and 2024. Maternal cytomegalovirus infections were classified and dated using centralized serological assessment. Children underwent standardized longitudinal follow-up, including audiological, neurological, behavioral, and neuroimaging evaluations, up to 48 months of age. Fetal brain magnetic resonance imaging was available for cases diagnosed antenatally. Outcomes of interest included hearing loss, neurodevelopmental impairment, and autism spectrum disorder. Among 642 children with confirmed congenital cytomegalovirus infection, 504 (78.5%) were exposed to a maternal primary infection with known timing. Of these, 288 (57.1%) followed first-trimester infection, 144 (28.6%) second-trimester infection, and 72 (14.3%) third-trimester infection. Long-term congenital cytomegalovirus-related sequelae, including hearing loss and neurodevelopmental impairment, were observed exclusively in children exposed to first-trimester maternal primary infection. Autism spectrum disorder was diagnosed in 11 children (1.7%), all of whom were symptomatic at birth; all cases following maternal primary infection occurred after first-trimester exposure. Compared with estimates from the general French population, prevalence in children with congenital cytomegalovirus was 4-fold higher (odds ratio, 4.25; 95% confidence interval, 1.63-21.33). In all children diagnosed with autism spectrum disorder, temporal lobe white matter abnormalities, especially in the temporal poles, were identified on postnatal magnetic resonance imaging and were present on antenatal imaging in fetuses who underwent prenatal magnetic resonance imaging. The review of all fetal magnetic resonance imagings from the prenatally diagnosed subgroup revealed that temporal lobe white matter abnormalities were present in a minority of cases and no child without temporal lobe abnormality developed autism spectrum disorder. In this large prospective cohort, adverse long-term outcomes following maternal primary infection were observed only after first-trimester exposure. Autism spectrum disorder occurred exclusively in this group and was consistently associated with temporal lobe white matter abnormalities. These findings support a time-restricted window of fetal vulnerability to cytomegalovirus-related brain injury and suggest that neuroimaging findings may contribute to prenatal and neonatal risk stratification and help inform prenatal and postnatal counseling.