Congenital cytomegalovirus (cCMV) is the most common congenital infection and is associated with sensorineural hearing loss, developmental delays, and visual impairment. The clinical presentation of cCMV is variable, and the majority (80%–90%) of newborns will never manifest any clinical symptoms. Given the clinical heterogeneity of cCMV infection, it is challenging to identify which newborns may benefit from testing. Recently, certain states have implemented a targeted screening program in which newborns who fail the newborn hearing screen are tested for cCMV. Clinicians and legislative bodies have been propelled into debates about the ethical and moral permissibility of a targeted cCMV screening approach. Those who oppose this screening approach describe undue burden on patients, families, and the health care system because the majority of newborns who fail the newborn hearing screen and have cCMV will not go on to have any sequelae related to cCMV, including hearing loss. However, those who support this screening approach cite the importance of early detection and ongoing surveillance for hearing loss and developmental delays in this high-risk group of newborns. This debate will be considered by experts in the field.

Cytomegalovirus (CMV) is the most common congenital infection, occurring in 0.6% of pregnancies or ∼23 000 births in the United States each year.1  As a leading cause of sensorineural hearing loss (SNHL), developmental delays, and visual impairment, congenital cytomegalovirus (cCMV) can significantly impact the health and well-being of children and their families.

The quandary of cCMV lies in its heterogeneous presentation, with long-term outcomes that vary from no effect at all to severe neurologic disability or death. Approximately 80% to 90% of newborns with cCMV will never have any clinical manifestations.2  At birth, only 10% of newborns with cCMV display symptoms, such as microcephaly, petechiae, and jaundice.2  Of these newborns who are symptomatic, 90% will have long-term neurologic sequelae.35  The remaining 90% of newborns with cCMV are asymptomatic at birth. For asymptomatic newborns, the risk of long-term sequelae is ∼10% to 15% and most commonly presents as isolated SNHL.68  Patients with cCMV have considerable variability in terms of presence and degree of hearing loss. cCMV has been attributed in 10% to 25% of all cases of childhood SNHL.3,8  Approximately 75% of children with CMV-related SNHL will have delayed-onset hearing loss and a normal newborn hearing screening (NBHS) test.3

cCMV must be diagnosed early (within 21 days) to distinguish congenital from acquired CMV infection.3  However, because of the clinical heterogeneity of cCMV, it has been challenging to identify which newborns may benefit from testing. There have been recent calls by parent and provider advocacy groups to implement cCMV screening programs to increase detection rates. Screening programs could be universal (involving all newborns) or targeted (aimed at a high-risk population or a group with a surrogate marker for cCMV infection). Currently, there are many hurdles to implementing universal screening, including poor diagnostic accuracy with testing on a dried blood spot and logistic complexities of collecting and testing urine or saliva samples from all newborns. Targeted cCMV testing, specifically of those newborns with a failed NBHS, has been enacted in several states. However, NBHS is imperfect, and >80% of newborns who fail this screening test will have normal follow-up audiologic testing.9  In addition, as mentioned above, most newborns with cCMV-related SNHL pass their NBHS test.

A debate has arisen as to whether this targeted screening approach is ethically permissible. The majority of newborns who fail an NBHS at birth and also have positive cCMV test results will go on to have neither hearing loss nor any sequelae of cCMV. Those who oppose screening also have concerns that unproven and potentially risky antiviral treatments might be offered to these families. Conversely, there has been debate as to whether implementing such a screening program in this high-risk population is morally obligatory given that early identification and audiologic and/or medical treatment of cCMV hearing loss could improve outcomes for the affected subset. We will work to unravel this ethical conundrum with input from experts in the field.

New state legislation has been proposed that would mandate testing of newborns who fail their NBHS for cCMV. As a newborn hospitalist, you are also the American Academy of Pediatrics chapter champion for your state’s Early Hearing Detection and Intervention committee. You are aware that other states have started targeted cCMV screening programs. You decide to convene an expert panel to discuss the pros and cons of supporting this legislation.

Congenital and other permanent SNHL can have significant health consequences, including failure to meet educational goals; decreased performance in speech, reading, and communication; and ultimately increased use of health care and emotional supports.10  In developed nations, genetic factors are the single most common offender causing permanent SNHL. cCMV infection, through vertical spread from mother to newborn, is the number 2 cause affecting 0.5% to 2% of all live births.2

cCMV infection may cause permanent and often progressive SNHL, with or without other sequelae of the disease. This hearing loss can be present at birth or may manifest later in childhood. Diagnosing cCMV is relatively easy through saliva and urine testing but only if done in the first 21 days of age. After this period, diagnosis becomes exceedingly difficult.

Targeted and universal screening approaches have been espoused by some members of the medical community and even incorporated into state law. A recent study of a targeted screening approach revealed that 57% of cCMV-related hearing loss was discoverable in the newborn period and attributable to cCMV.2  However, it missed ∼43% of late-onset cCMV-related hearing loss. From a pediatric otolaryngologist viewpoint, targeted screening is helpful but not complete. Targeted CMV screening is a start, diagnosing a significant number of otherwise idiopathic hearing loss cases that previously would not have been defined.

A targeted screening approach has the ability to minimize further invasive and costly tests (namely genetic tests and/or imaging) for those it captures. It allows audiologists and pediatric otolaryngologists the opportunity to more accurately advise their patients regarding the nature of their hearing loss and allows them to recommend timely audiologic monitoring tests. When cCMV-related SNHL is diagnosed in a timely manner, children may be able to maximize early intervention (EI) services and gain access to current infectious disease treatments. Finally, caregivers who were perpetually unsatisfied at not knowing the cause for their child’s hearing problem may be provided a level of peace and satisfaction not previously afforded.

Antiviral medications that can inhibit the replication of CMV have been routinely used for the treatment of CMV infections since 1988. An increasing number of studies have revealed that newborns with symptomatic cCMV (ie, newborns with multiple cCMV-related abnormalities at birth) who are treated with antiviral agents, such as ganciclovir or valganciclovir, have improved long-term audiologic and neurocognitive outcomes.11  It is not known, however, if infants who are detected at older ages (eg, after 1 month of life) would receive similar benefit from antiviral medications. Thus, it is critical to not only distinguish infections that occur during the prenatal period but also identify which newborns infected prenatally are more likely to develop adverse neurocognitive outcomes because these newborns not only would benefit from antiviral medications but also would need closer neurodevelopmental monitoring.

One screening strategy that has been implemented in several states in the United States is the targeted screening approach. One of the key advantages of this approach is that it allows for early identification of cCMV in the subgroup of newborns who may otherwise not have been detected (ie, asymptomatic cCMV at birth) yet who remain at increased risk of developing progressive cCMV-related disabilities. It is not known if antiviral medications will provide any benefit to newborns with cCMV who, aside from an initial abnormal hearing screen, are asymptomatic at birth. Two clinical trials sponsored by the National Institutes of Health are currently underway to establish this. The randomized controlled trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants (ValEAR) study, led by Dr Albert Park from the University of Utah, is a multicenter double-blind, randomized, placebo-controlled trial to determine if hearing-impaired newborns with otherwise asymptomatic cCMV have better hearing and language outcomes if they receive valganciclovir antiviral treatment of 6 months’ duration.12  Newborns are currently being enrolled in this study, which is estimated to be completed in 2022. The second ongoing trial is being led by a team of investigators at the National Institute of Allergy and Infectious Diseases and is scheduled to be completed in 2024. It is an open-label, multicenter trial aimed at evaluating the efficacy of 4 months of valganciclovir for the prevention of SNHL in newborns with no outward manifestations of cCMV, including normal hearing.13  However, even in the absence of an efficacious antiviral medication, data suggest that the targeted screening approach is cost-effective at the societal level.14  This is largely because cCMV-related disabilities are often progressive. Thus, all newborns with cCMV, even those who are asymptomatic at birth, are at an increased risk for future hearing and vision loss and developmental delays. Thus, knowing that a newborn has cCMV provides clinicians with the opportunity to risk-stratify and implement more intensive neurocognitive and audiologic surveillance during key developmental stages. This would, in turn, allow for earlier detection of developmental delays, a substantial advantage on its own, because numerous studies have demonstrated better short- and long-term outcomes when developmental problems are recognized and intervention services are provided in a timely manner.15,16

There is no question that a targeted screening approach is likely to miss a large proportion of the newborns who go on to have complications of cCMV. However, we should not “throw out the baby with the bathwater”; we should not get rid of something that has real value in our efforts to eliminate something that has not yet been perfected. This screening approach, although imperfect, provides a reasonably good compromise and is clearly cost-effective. Given the significant health and economic impact of cCMV, any strategy that maximizes early detection and provides opportunities for the initiation of timely pharmacologic and nonpharmacologic interventions will lead to better outcomes and should be encouraged.

Proposed screening tests should meet criteria established by the World Health Organization (WHO). The WHO requires that screening tests meet 11 criteria (Table 1).17  First, the condition should be an important public health problem. The rates of cCMV-related hearing loss are ∼0.1% of the population, similar to rates of serious congenital heart disease that are detected by screening alone. Because hearing loss has significant morbidity and lifelong effects, screening would meet this criterion. Second, there should be a treatment of the condition. Audiologic support, including cochlear implants, and EI services can partially mitigate the effects of cCMV-induced hearing loss but are not curative. The efficacy of antiviral treatments, such as valganciclovir, for patients with asymptomatic cCMV-related hearing loss is not known. As mentioned by Dr Oliveira, a large multicenter trial is ongoing. Third, centers that can provide treatment should be available. Although these centers do exist, it is unclear if there would be sufficient pediatric audiologic capacity to manage the newborns identified who would merit serial follow-up.

Table 1

Characteristics of a Screening Test

Characteristics
The condition sought should be an important health problem.
There should be an accepted treatment of patients with recognized disease.
Facilities for diagnosis and treatment should be available.
There should be a recognizable latent or early symptomatic stage.
There should be a suitable test or examination.
The test should be acceptable to the population.
The natural history of the condition, including development from latent to declared disease, should be adequately understood.
There should be an agreed-on policy for determining whom should be treated as patients.
The cost of case finding, including diagnosis and treatment of patients diagnosed, should be economically balanced in relation to possible expenditure on medical care as a whole.
Case finding should be a continuing process and not a once-and-for-all project.
The test used should be sensitive.
Characteristics
The condition sought should be an important health problem.
There should be an accepted treatment of patients with recognized disease.
Facilities for diagnosis and treatment should be available.
There should be a recognizable latent or early symptomatic stage.
There should be a suitable test or examination.
The test should be acceptable to the population.
The natural history of the condition, including development from latent to declared disease, should be adequately understood.
There should be an agreed-on policy for determining whom should be treated as patients.
The cost of case finding, including diagnosis and treatment of patients diagnosed, should be economically balanced in relation to possible expenditure on medical care as a whole.
Case finding should be a continuing process and not a once-and-for-all project.
The test used should be sensitive.

Adapted from Wilson JG, Jungner G. Principles and Practice of Screening for Disease. Geneva, Switzerland: World Health Organization; 1968.

The fourth WHO criterion is that the disease has a latent, asymptomatic phase, which is the case for any type of newborn hearing loss, including the subtype associated with cCMV. However, a failed NBHS prompts referral for audiologic follow-up and EI services if the hearing loss is confirmed. It remains unclear if diagnosing cCMV in these situations has additional benefit. Universal screening for cCMV could detect newborns who may benefit from later audiologic monitoring if they have the infection but pass their NBHS. However, as stated previously, only 10% to 15% of newborns with asymptomatic cCMV go on to manifest hearing loss, and half of these would pass their NBHS. Universal cCMV screening to detect a true need for later audiologic follow-up would be beneficial to 3 of every 10 000 newborns screened, yet it would expose 20-fold more infants to unneeded audiologic follow-up and, potentially, to medications with known risks.

The fifth WHO criterion concerns the availability of a test for the condition. CMV polymerase chain reaction (PCR) testing of saliva samples has 98% to 100% sensitivity and minimal collection barriers.18,19  Urine PCR testing is also sensitive but has minor collection barriers. Sixth, the test should be acceptable to the population. Saliva and urine testing are likely acceptable; however, many infants would receive serial audiologic follow-up and ultimately have normal hearing, which could place an undue burden on families. The seventh criterion is that the natural history of the disease is understood. This is only partially true for cCMV because it is not understood which 10% to 15% of newborns with asymptomatic cCMV will go on to have hearing loss and to what degree they will experience hearing loss and neurodevelopmental delays. The eighth criterion requires an agreed-on policy for whom to treat. Although audiologic follow-up for newborns with failed hearing screens alone (with or without cCMV) is not controversial, the use of valganciclovir is controversial for those with asymptomatic cCMV. The efficacy of valganciclovir for newborns with asymptomatic cCMV is currently being studied in a multicenter randomized trial, and there are known risks to the medication. Valganciclovir does mitigate hearing loss in those with symptomatic cCMV on the basis of a large randomized trial.11  Finally, the test should be sensitive, and buccal swab PCR and urine testing are both >90% sensitive for viral detection. Targeted cCMV screening meets many but not all of the WHO criteria for a good screening test.

In addition to meeting the WHO criteria related to disease burden, the benefit of early detection, test performance, acceptability to a population, and the implementation and success of any screening program requires consideration of cost.20  There is literature on the cost-effectiveness of cCMV screening in the United States that supports the implementation of newborn cCMV screening, with reportedly greater cost savings with targeted screening compared with universal screening.14,21

In a study by Bergevin et al,21  investigators in Utah used state government administrative data and multihospital accounting data to estimate and compare costs and benefits of a targeted screening approach for cCMV in the Utah newborn population.14  Cost included the (1) administrative costs of education and development of the screening program and (2) medical costs of the CMV screening test and treatment of newborns who tested positive for CMV.14  Much of the cost from screening and treatment of newborns who are congenitally infected and hearing impaired is expected to come from antiviral therapy and cochlear implantation.14  The investigators found that if antiviral treatment succeeds in mitigating hearing loss for one infant per year, the public savings will offset the public costs incurred by screening and treatment. However, if the antiviral treatment proves to be unsuccessful, the program represents a net cost but may still have nonmonetary benefits, such as accelerated achievement of developmental milestones.14  The investigators concluded that CMV education and treatment program costs are modest and reveal some potential for cost savings.14  There is uncertainty in the cost estimates because it is presently unknown if valganciclovir will be effective for cCMV-isolated hearing loss. If it is effective, both the effect size and number needed to treat are still unknown at present.

In another study by Gantt et al,14  investigators estimated the cost-effectiveness of universal and targeted newborn cCMV screening programs compared with no cCMV screening using models created from rates and outcomes of prospective cohort studies of newborn cCMV screening in US postpartum care and early hearing programs.21  The cost of identifying 1 case of hearing loss due to cCMV was $27 460 by universal screening compared with$975 by targeted screening.21  Half of newborns infected with cCMV would be missed by targeted screening. The investigators concluded that newborn screening for cCMV infection appears to be cost-effective under a wide range of assumptions.21  Universal screening offers larger net savings and the greatest opportunity to provide directed care. However, targeted screening also appears to be cost-effective and requires testing for fewer newborns.21

There would be few risks to increased audiologic monitoring for newborns who test positive for cCMV at birth, regardless of whether cCMV is detected by universal or targeted screening. The main potential risk associated with the treatment of newborns who test positive for cCMV would be the potential for off-label use of valganciclovir in cases of asymptomatic cCMV before the completion of an ongoing large multicenter randomized controlled trial. Even if the trial reveals a modest improvement in hearing with valganciclovir, the treatment of newborns who have asymptomatic cCMV with the antiviral agent means that 85% to 90% of the treated newborns would not have experienced eventual hearing loss but would be exposed to the risks of treatment. At present, the trial is still ongoing, with completion expected in 2024. Given that valganciclovir efficacy for hearing improvement in infants with symptomatic cCMV is modest, the expectation is that the impact in the asymptomatic population will also be modest.11

In conclusion, it is not clear that targeted cCMV screening meets the WHO criteria for an appropriate screening test. There is no approved treatment of newborns with asymptomatic cCMV apart from the audiologic follow-up that would already occur on the basis of the failed hearing screen alone. If targeted cCMV screening is adopted, it is not clear whether there is a pediatric audiology capacity to handle the increased referrals because 17 to 18 of 20 additional referrals will not go on to have cCMV-related hearing loss.

From an individual patient, caregiver, and clinician perspective, the risks of implementing a statewide targeted cCMV screening approach outweigh the benefits. In pediatrics, there are countless examples in which testing and treatment are available options and yet are not pursued because of an imbalance of this risk/benefit ratio. For example, a clinician could obtain a radiograph for all patients who present with an ankle injury. However, given the risks of radiation and cost, careful history and physical examination maneuvers are performed to determine who would most benefit from imaging. For clinicians, the practice of weighing risks and benefits becomes instinctual over time so that all decisions are rooted in this principle.

As mentioned earlier, a majority of newborns with cCMV will never have any clinical manifestations of the infection. Therefore, testing and treatment in this population only serve to increase awareness of the diagnosis but do not provide additional benefit to the patient. With the added knowledge of a cCMV diagnosis, these patients who are asymptomatic and their families will interface with the health care system to undergo additional testing and subspecialty evaluation (including ophthalmology, infectious disease, developmental specialists, and audiology). However, given the low incidence of disease-related sequelae, this investigational odyssey becomes superfluous, and parents may have increased anxiety and/or begin to view their child as sick. Vulnerable child syndrome can have lasting adverse effects on the parent-child relationship; the parent may demonstrate excessive concern, and the child can develop symptoms that reinforce these anxieties.22,23  There is also the risk that a positive CMV test result for a newborn with hearing loss may lead to premature closure of the diagnostic workup when there are, however, many causes of congenital SNHL. Accurate diagnosis of the underlying etiology of SNHL is important because genetic causes have implications for other family members and/or may be associated with other anomalies. In addition to the clinical aspects, the individual financial cost associated with this approach is not negligible and includes monies lost because of travel time, missed work, and health care resource use (laboratory testing, potential neuroimaging, numerous medical appointments). For the clinician, the increased time and effort to coordinate care for these patients may be considerable. Although it is true that detection may result in improved outcomes for some, the large majority of newborns who screen positive will not benefit despite an exhaustive evaluation.

As clinicians, we work to identify a diagnosis to offer treatment to cure an illness. In the case of asymptomatic cCMV, a proven and effective treatment option does not yet exist. Antivirals that bear potentially significant risks are currently being offered off-label to patients with asymptomatic cCMV. For individual patients, the short-term side effects include neutropenia (∼20%), thrombocytopenia (6%), hepatitis (6%), and nephrotoxicity (<1%), necessitating periodic (and painful) laboratory monitoring.11,24  If clinically significant, these could lead to a domino effect in which additional treatments are prescribed to treat iatrogenic symptoms. Long-term side effects of the antiviral agents have been documented in animal studies and include potential teratogenicity and gonadotoxicity.25,26  Additionally, for clinicians who offer and initiate off-label antiviral agents, there is risk of both moral and legal sequelae if untoward side effects were to occur. Finally, it will be challenging to monitor the therapeutic effect of antiviral therapy in the asymptomatic cCMV population because the majority of patients will never develop sequelae, regardless of treatment. Therefore, the determination of successful treatment in these asymptomatic patients will prove arduous without a measurable improvement or end point.

In summary, when reflecting on the potential value added in implementing a targeted screening approach for cCMV, the risks outweigh the benefits when the perspective of an individual patient, caregiver, or clinician is considered.

An expert panel highlighted the potential implications of a targeted screening approach in which a failed NBHS test is used as the impetus to test for cCMV. Those who oppose the implementation of targeted cCMV screening argue that this approach is an added burden given that it will miss a large proportion of newborns with cCMV and that the majority of newborns with cCMV will never have any clinical manifestations. The opposition also cites the lack of a proven treatment of newborns with asymptomatic cCMV. Alternatively, experts who support a targeted cCMV screening approach describe the possible improved neurocognitive outcomes associated with an early diagnosis that allows for ongoing surveillance and access to community services. Supporters also discuss the cost-effectiveness of the approach and the possibility of treatment options pending the results of the ValEAR trial. In summary, using a targeted screening program for cCMV may confer benefits to patients and society as a whole; however, it would not be without risks. Outcomes from the ValEAR trial may help tip the scale either to support or oppose targeted cCMV screening because we will better understand the risks and benefits of valganciclovir in the treatment of asymptomatic cCMV. Researchers should additionally investigate both the financial and psychosocial costs of cCMV diagnosis and treatment, which could be done through the natural experiment that results from only certain states implementing a targeted screening program. Each state should continue to carefully weigh the risks and benefits with involvement from a multitude of stakeholders.

All authors conceptualized and designed this work, drafted the initial manuscript, reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

Dr Larson’s current affiliation is Department of Pediatrics, University of California, San Francisco, San Francisco, CA.

FUNDING: No external funding.

• cCMV

congenital cytomegalovirus

•
• CMV

cytomegalovirus

•
• EI

early intervention

•
• NBHS

newborn hearing screen or screening

•
• PCR

polymerase chain reaction

•
• SNHL

sensorineural hearing loss

•
• WHO

World Health Organization

•
• ValEAR

Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants

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## Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.