Congenital Cytomegalovirus—The Next Newborn Screening Frontier?

Cytomegalovirus (CMV) is the most common infectious cause of congenital sensorineural hearing loss, which leads to speech and language delay. The virus also causes microcephaly, developmental disability, and vision abnormalities. Because early detection is key to giving affected children the healthiest possible start in life and studies have shown that an antiviral drug may improve outcomes, many hearing loss experts would like to see routine CMV screening added to state newborn screening panels. Newborn CMV screening could detect many infected infants who hear well enough to pass hearing screens at birth but later develop hearing loss, they argue. Utah and Connecticut currently offer targeted screening for newborns who fail routine hearing tests.

Yet the prospect of CMV newborn screening remains controversial. Despite studies deeming it cost-effective and research linking antiviral treatment to better outcomes, some hearing loss experts say that current targeted screening programs miss many asymptomatic infants, while no studies show antiviral drugs improve longer-term hearing outcomes in either symptomatic or non-symptomatic babies. Another factor that had been holding back the concept of CMV newborn screening was that inexpensive, rapid screening tests did not exist. But now the Centers for Disease Control and Prevention (CDC) recommends polymerase chain reaction (PCR) testing of saliva as the standard diagnostic test for congenital CMV, providing a high-throughput method of detecting the virus.

This somewhat muddled picture of CMV screening and treatment benefits appears to be clarifying as promising study data come out. Most recently, University of Utah researchers looked at the effects of that state’s first-in-the-nation CMV newborn screening program, which requires that all babies who fail newborn hearing screening undergo CMV testing within the first 3 weeks of life unless a parent declines. This initiative identified 14 CMV-positive infants, six of whom had hearing loss. Overall, 77% of asymptomatic babies who failed newborn and subsequent hearing screening went on to have diagnostic CMV evaluations within 90 days of birth, up from 56% before the legislation went into effect. The authors concluded that incorporating CMV screening into an established newborn hearing screening program is a “viable option” in identifying CMV-infected babies (Pediatrics 2017;139:e20160789).

Meanwhile, the CMV and Hearing Multicenter Screening (CHIMES) study evaluated how well targeted CMV screening would identify CMV-infected babies. After conducting both congenital CMV testing and newborn hearing screening in nearly 100,000 babies, the investigators found that relying first on failed newborn hearing screening identified 57% of babies who had CMV-related hearing loss. However, this targeted approach missed 43% of neonates who had CMV-related hearing loss as well as babies at risk for late-onset hearing loss (Pediatrics 2017;139:e20162128).

In another recent analysis, the CHIMES investigators determined that both universal and targeted screening would be cost-effective. They estimated the cost of identifying one CMV case by universal screening would range from $2,000–$10,000, including PCR testing of oral swabs and confirmatory urine PCR testing on initial positive results. The researchers calculated screening and subsequent treatment would yield net per baby savings ranging from $10.66 to $27.31 in targeted screening scenarios to $21.34 to $37.97 in universal screening scenarios (JAMA Pediatr 2016;170:1173–80).

Cost is a criterion for recommendation in favor of either targeted or universal screening by the Department of Health and Human Services Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SAC). SAC advises the secretary on additions to a panel of recommended conditions that states usually decide to include in their newborn screening programs.

Another key SAC criterion is an available, viable treatment for the condition being considered for newborn screening. Development of the orally administered antiviral drug valganciclovir hydrochloride is driving much of the discussion of CMV newborn screening, according to Sallie Permar, MD, associate professor of pediatrics at Duke University School of Medicine in Durham, North Carolina.

Based on accumulated study data, Permar and CHIMES authors agree that it’s time to implement universal screening, or at least targeted screening. “Testing for congenital CMV is readily available, simple, and relatively inexpensive,” said CHIMES investigator Suresh Boppana, MD, professor of pediatrics at University of Alabama (UAB) School of Medicine in Birmingham. His fellow UAB pediatrics professor and CHIMES researcher, Karen B. Fowler, DrPh, concurred. “We should do targeted screening now with the goal of implementing universal screening in the near future,”
she added.

CMV occurs in 1 in 150 births, making it more common than any condition SAC now recommends for inclusion in state newborn screening programs, Permar pointed out. Albert Park, MD, also believes there is sufficient data for adding targeted screening to state panels. A senior author of the study examining Utah’s CMV screening legislation and chief of pediatric otolaryngology and professor of surgery and of pediatrics at University of Utah, Park called himself an advocate of universal screening but said, “The question is whether we’re ready to go to that step.”

Park pointed to several issues that need to be resolved before widespread CMV newborn screening occurs. Because most state newborn screening tests look for genetic conditions and are performed on dried bloodspots, states would need new infrastructures to collect and test saliva or urine. These specimens currently make better samples than blood because more virus is shed in them, he explained.

CHIMES investigators identified only 30% of infected children through bloodspots, but investigators at CDC, the Minnesota Department of Health, and the University of Minnesota are comparing newer, more sensitive bloodspot methods to saliva-based methods in 30,000 newborns at several Minneapolis area hospitals, according to Sheila Dollard, PhD, a microbiologist at CDC.

Park added that more data are needed on the effectiveness and safety profile of valganciclovir in children, specifically on its long-term, persistent benefits, safety for newborns, and long-term adverse effects. No such data currently exist, and the U.S. Food and Drug Administration has not approved the drug for congenital CMV infections.

Meanwhile, questions remain about the majority—up to 80%—of CMV-positive newborns who will not develop hearing loss. “We don’t know what to do with those kids. Most CMV-positive asymptomatic children don’t get follow-up,” Park noted.

He is about to start a multi-institutional, double-blinded study of CMV-positive infants with hearing impairment who will receive 6 weeks of valganciclovir treatment or placebo. The study will measure hearing, speech, language, and safety outcomes. Other multicenter studies are looking at how valganciclovir improves hearing assessments in hearing-impaired CMV-positive children ages 1 month to 3 years and whether the drug prevents later-onset hearing loss in older, asymptomatic CMV-positive infants.

SAC has been monitoring research that would inform wider newborn screening for CMV, but the committee has not received a request to review evidence, said its chair, Joseph A. Bocchini Jr., MD, professor and chairman of pediatrics and director of the clinical virology laboratory at Louisiana State University Health Sciences Center in Shreveport.

The recent finding that targeted screening misses a large proportion of CMV-positive infants at risk for hearing loss, “leads us toward looking at universal screening even if costs are higher,” said Bocchini, who called recent estimates of screening costs “within range,” considering CMV’s severity and the availability of a potential treatment for it.

However, Bocchini identified several unanswered questions SAC would likely consider before issuing a recommendation. A commentary published in Pediatrics highlights the same issues, which include how follow-up of asymptomatic infants should occur (Pediatrics 2017;139:e20163837). Although Utah offers asymptomatic children valganciclovir, the research that looks at the drug’s safety and effectiveness in this population will take years to deliver data, the commentary adds.

At this time, no evidence demonstrates CMV newborn screening’s feasibility and affordability for state public health systems, according to both the commentary and Bocchini. “There is no prospective population-based study done in a public health lab, so that we can see the outcomes are the same as in the clinical lab. That’s a key criterion for us,” said Bocchini. “Remember, universal newborn screening means four million babies a year. It’s our responsibility to look at all of the issues and costs.”

Deborah Levenson is a freelance writer in College Park, Maryland.+Email: [email protected]