NEWBORN SCREENING FOLLOW-UP STUDY OF CONGENITAL CYTOMEGALOVIRUS (CCMV) INFECTION

Congenital cytomegalovirus (cCMV) is the most common congenital infection and is estimated to occur in 0.6% of all pregnancies, impacting ~23,000 births in the United States each year. This makes cCMV more common than most conditions currently on the Recommended Uniform Screening Panel (RUSP). The manifestations of cCMV are highly variable and include sensorineural hearing loss (SNHL), developmental delays, and visual impairment. The extreme presentation at birth is one of microcephaly, hepatosplenomegaly, petechiae, seizures, and jaundice, occurring in ~10-15% of infected newborns and resulting in infant death in 5-10% of those with symptoms. In addition, of those newborns who are symptomatic, 50-90% will have long-term neurologic and developmental complications. However, the remaining ~90% of newborns with cCMV will be clinically asymptomatic at birth. For asymptomatic newborns, the risk of long-term sequelae is ~10% to 15%, which often presents as isolated SNHL, and may not be detected through newborn hearing screening as it may be late onset or progressive, presenting through age 5 years.
If an infant diagnosed with cCMV develops symptoms, treatment with antiviral medications (IV ganciclovir, oral valganciclovir) has been shown to improve outcomes with regard to hearing and development, although some of these gains have not been sustained in more recent reviews. However, transient neutropenia is a known side effect of the treatment, which has led some experts to not routinely recommend antiviral treatment of asymptomatic infected infants. Nonetheless, identification of asymptomatic infants with cCMV allows for neurodevelopmental evaluation, follow-up, and monitoring for hearing loss, with prompt treatment to prevent language delays or language loss in this high-risk population. Frequent audiologic monitoring at 6-month intervals has been recommended in this population until age 5 years, with more frequent monitoring every 3 months when hearing levels are changing or until the child is talking. Cochlear implants are recommended for children with acquired severe hearing loss to improve speech and language outcomes. NBS screening for cCMV, whether population-wide or targeted only to infants who fail their newborn hearing screening, raises important ethical and public health considerations, including concerns about both under- and over-diagnosis, overtreatment of asymptomatic screen-positive infants, parental anxiety and vulnerable child syndrome, and the added burden on state public health programs.
The recent RUSP nomination for cCMV was returned to the submitters for lack of evidence including the need for more data on how to identify which cases will benefit from treatment, uncertain clinical utility afforded by population-wide early diagnosis relative to reflex testing for failed hearing screens, and the recommended follow-up and treatment protocol for screen-positive infants. A prospectively identified cCMV-positive cohort of infants with longitudinal data collection would help record the natural history of the infection, thereby enhancing our understanding of outcomes and of potential risk and modifying factors that predict outcomes for these newborns.
The Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) is interested in expanding on the awarded cCMV pilot study by supporting a follow-up study of screen positive infants to better understand the impacts of incorporating cCMV screening into NBS programs, in order to address important evidence gaps for state programs considering adding cCMV screening to their NBS program. This effort will support additional follow-up data collection on screen-positive infants to gather longitudinal data on audiologic, developmental, and neurological outcomes, as well as measurements of quality of life for infected infants and their caregivers.

Grant Number: 75N94021D00018-0-759402300001-1
NIH Institute/Center: NIH
Principal Investigator: MICHELE CAGGANA