Neurodevelopmental Outcomes for CMV Infections Identified by Newborn Screening

ABSTRACT A remarkable change in the approach to the diagnosis, evaluation, and management of congenital cytomegalovirus (cCMV) infection has occurred in recent years. Driven by the advent of universal newborn screening for cCMV, newborns with this infection that would have never been clinically recognized in past years are now being identified, evaluated, and monitored – primarily for delayed-onset sensorineural hearing loss (SNHL). SNHL is the major known complication of cCMV, occurring in up to 12% of infants with this infection. However, the advent of universal screening has created challenges, and exposed significant knowledge deficits about the natural history of cCMV. Conventional thinking has been that the majority of cCMV infections are asymptomatic (AcCMV), and except for those children that develop SNHL, the prognosis for a normal outcome is favorable. This assumption is based on small, often uncontrolled studies. The long-term neurodevelopmental and neurocognitive outcomes of AcCMV have never been examined in a well-powered and unselected population of infants diagnosed in the context of universal screening. To address these knowledge deficits, and better understand the potential range of outcomes in AcCMV, this proposal aims to address three specific aims. First, we aim to determine if infants with AcCMV have reduced white matter structural coherence when compared to control infants. Our control infants will come from the NIH-funded HEALthy Brain and Child Development (HBCD) Study, which is advancing the field of cognitive neuroimaging by developing and validating significantly faster and higher resolution acquisition protocols, resulting in more robust infant imaging data. Second, we will determine if infants with AcCMV have reduced performance on longitudinal neurocognitive assessments when compared to HBCD control infants. Key features will be standardized scores of cognitive, language, and motor skills, as well as executive function and emotion regulation skills. Third, we aim to explore new scientific avenues by determining if AcCMV-associated SNHL can be predicted with brain MRI. Multi-shell diffusion imaging data will measure axonal microarchitecture and fMRI passive listening tasks will measure task-specific BOLD responses. This aim addresses a major challenge in the field of cCMV, and the public health and clinical management implications are extensive. Our over-arching hypothesis is that infants with AcCMV do, indeed, have a long-term phenotype that has heretofore been unrecognized because of the limited sensitivity of previous approaches. This work will inform and direct the future of newborn cCMV screening programs, and has implications for clinical management, including antiviral therapy. The proposed project will also enhance our understanding of this ubiquitous but understudied congenital viral infection.