Congenital cytomegalovirus (cCMV) infection is the leading nongenetic cause of sensorineural hearing loss (SNHL) in children.1 In the United States, cCMV occurs in an estimated 5 per 1000 live births.1 However, most cCMV infections remain undiagnosed. Newborns are usually tested for cCMV because of abnormal prenatal ultrasound findings, clinical suspicion at birth, maternal history of CMV infection during pregnancy, or referral from newborn hearing screening. Approximately 10% of infected infants present with clinical findings, such as purpura, petechiae, jaundice, hepatosplenomegaly, retinitis, or microcephaly, at birth.1 Up to 50% of symptomatic infants and 15% of asymptomatic infants present with SNHL either at birth or with delayed onset, which can be stable, fluctuating, or progressive.1
Infants diagnosed with cCMV may be offered antiviral treatment, through off-label use, to preserve hearing and ameliorate developmental outcomes. The American Academy of Pediatrics recommends either intravenous ganciclovir or oral valganciclovir (ganciclovir prodrug) only for infants with moderately to severely symptomatic cCMV disease who can start treatment within the first month of life.1 SNHL is usually considered a sequela rather than a clinical finding to categorize symptomatic cCMV, and antiviral treatment is not recommended for infants with isolated SNHL.1,2 However, many European experts classify infants with isolated SNHL as having severely symptomatic cCMV disease and recommend antiviral treatment.3
Despite the American Academy of Pediatrics’ recommendation, antiviral treatment in infants with cCMV without clinical findings has grown rapidly in the United States.4 Comparing insurance claim data from 2009 through 2015 and 2016 through 2019, valganciclovir prescriptions for infants with cCMV diagnoses but no reported cCMV-related clinical findings recorded increased nearly 2-fold among those with SNHL and 3-fold among those without SNHL.4 US electronic health records data during 2010–2021 showed that, among infants with cCMV diagnoses who were treated with antiviral medication, approximately one-quarter first received intravenous ganciclovir, usually within the first month of life, whereas, among those who were only prescribed oral valganciclovir, treatment started after the first month of life in nearly 60%.5
In 2 clinical trials conducted by the Collaborative Antiviral Study Group (CASG) and sponsored by the National Institute of Allergy and Infectious Diseases, ganciclovir or valganciclovir, when started within the first month of life, appeared to improve hearing and developmental outcomes modestly up to 24 months of age for infants with symptomatic cCMV and central nervous system involvement.6,7 Observational studies have also found that infants with symptomatic cCMV and hearing loss who were treated with antiviral agents showed greater improvement or less deterioration in hearing, especially those with mild to moderate hearing loss at baseline.8 Observational studies, however, may be limited by retrospective design, lack of control groups, small sample sizes, and the high heterogeneity of study participants, treatment duration, audiologic methods, or definitions of change in hearing thresholds.
Although current clinical consensus seems to favor antiviral treatment in infants with symptomatic cCMV, important clinical questions remain unanswered. First, is antiviral treatment protective against hearing deterioration when initiated after the first month of life, as is common practice?5 One placebo-controlled trial of valganciclovir in children with delayed-onset SNHL who started treatment between 1 month and 3 years of age found worsened hearing in 23% (6/26) of ears in the treatment group compared with 4% (1/28) of ears in the placebo group.9 A second question is whether improvements in hearing associated with antiviral treatment initiated in the neonatal period persist beyond early childhood. Only 1 study has documented hearing outcomes at ≥12 years of age,10 finding that children with symptomatic cCMV who received ganciclovir for 6 weeks in infancy had no better hearing in adolescence than those who were untreated.10
Finally, are infants with symptomatic cCMV who have normal hearing and receive antiviral treatment at lower risk of developing hearing loss? To examine this question, we reviewed data from the first 2 CASG trials on hearing outcomes for normal-hearing ears at study enrollment (baseline).6,7 In the first trial, hearing loss was diagnosed between baseline and ≥12 months (average, 24 months) in 35% (6/17) of normal-hearing ears of infants who received ganciclovir for 6 weeks, compared with 53% (9/17) of normal-hearing ears of untreated infants.6 The second trial assessed the overall change in hearing from baseline to follow-up without stratification by hearing status at baseline.7,11 In the 6-month and 6-week valganciclovir treatment arms, hearing loss onset was diagnosed from baseline to follow-up assessment as follows: in 9/55 (16%) and 6/55 (13%) ears at 6 months, respectively, 2/54 (4%) and 7/47 (15%) ears at 12 months, and 5/53 (9%) and 3/38 (8%) ears at 24 months. The 12-month assessment suggests a temporary improvement in hearing for those in the 6-month arm. Although differential loss of follow-up at various time points complicates the interpretation of the findings, the study does not provide evidence that antiviral treatment preserves hearing in normal-hearing ears. The lower proportion of hearing loss onset in infants who received valganciclovir therapy for 6 weeks in the second trial relative to those who received ganciclovir in the first trial (8% to 15% vs 35%) could reflect differences in sample composition as well as loss to follow-up.6,7 For instance, in the first trial, all infants had central nervous system involvement per inclusion criteria compared with 59% of infants treated with valganciclovir for 6 weeks in the second trial.
Currently, the evidence of the efficacy of antiviral medication on hearing preservation in infants with asymptomatic cCMV is also lacking. An open-label trial to assess valganciclovir treatment of hearing loss prevention in infants with asymptomatic cCMV was recently suspended because of safety concerns.12 A study in the Netherlands assessed whether 6-week valganciclovir therapy prevented hearing deterioration by 1 year of age among infants with cCMV and isolated SNHL compared with no treatment, but results are not yet available.13 Retrospective cohort studies including treated and untreated infants with cCMV stratified by severity or clinical findings at birth could provide preliminary evidence.
Ultimately, while awaiting more informative data from future studies, clinicians and families of infants with cCMV are left to grapple with the question as to whether the benefits of valganciclovir treatment outweigh the risks. Hematologic adverse events occur in 29% of infants with cCMV treated with valganciclovir, the most common of which is neutropenia.14 Yet most occurrences happen in the first 6 weeks of treatment and resolve by either lowering the dose or holding the medication to allow for absolute neutrophil count recovery before restarting antiviral agents.7,14 In the second CASG trial, after all participants were treated with valganciclovir for 6 weeks, those randomized to continue valganciclovir through month 6 of the study did not have a higher risk of neutropenia than those who received placebo during the same period.7 Even so, frequent safety laboratory studies by venipuncture are necessary throughout the 6-month treatment course, which can be challenging to draw from an infant. Obtaining and administering valganciclovir to an infant is also not straightforward because the medication needs to be compounded, refrigerated, and administered twice daily.
Considering the sparse data on benefits and the known risks of valganciclovir, shared decision-making becomes extremely important. Even if antiviral treatment does not change long-term hearing outcomes, if it delays the onset or progression of SNHL in the prelingual period, children could potentially experience improved speech and language outcomes.15 It is important for clinicians to educate families on how their child might have been affected by cCMV and that some neurologic changes that have already occurred in utero may not be reversible with antiviral treatment. Communicating that antiviral agents have at best a modest impact on developmental outcomes may help anchor the discussion of treatment options with realistic expectations. Any treatment plan for an infant with cCMV, regardless of antiviral use, should include a broad approach to clinical management including anticipatory guidance, social support, hearing and developmental monitoring, and early intervention therapies.1–3
Drs Lanzieri and Grosse conceptualized the study and reviewed the data, 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 Pesch critically reviewed and revised the manuscript, approved the final manuscript as submitted, and agrees to be accountable for all aspects of the work.
The findings and conclusions are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURES: Dr Pesch serves on the Board of Directors of the National CMV Foundation, which played no role in the conceptualization, writing, or finalizing of this work. The other authors have indicated they have no potential conflicts of interest to disclose.
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