Treatment of congenital cytomegalovirus infection

Gyu Hong Shim

doi:10.3345/cep.2022.01032

Clin Exp Pediatr > Volume 66(9); 2023

Shim: Treatment of congenital cytomegalovirus infection

Review Article

Neonatology (Perinatology)

Treatment of congenital cytomegalovirus infection

Gyu Hong Shim, MD, PhD

Department of Pediatrics, Inje University Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea

Corresponding author: Gyu Hong Shim, MD, PhD. Department of Pediatrics, Inje University Sanggye Paik Hospital, Inje University College of Medicine, 1342 Dongil-ro, Nowon-gu, Seoul 01757, Korea Email: peddoc@paik.ac.kr

Received August 16, 2022 Revised November 26, 2022 Accepted December 7, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Clinical and Experimental Pediatrics 2023;66(9):384-394.

Published online: December 28, 2022

DOI: https://doi.org/10.3345/cep.2022.01032

Abstract

Congenital cytomegalovirus (CMV) is the most common cause of congenital infection worldwide, the most common nongenetic cause of sensorineural hearing loss in children, and a cause of neurodevelopmental disorders in the brain. Infants with symptomatic congenital CMV infection may benefit from hearing and neurodevelopmental outcomes, particularly if antiviral treatment is initiated within the first month of life. Infants with life-threatening symptoms are recommended to receive 2–6 weeks of intravenous ganciclovir and then switch to oral valganciclovir, and those without life-threatening symptoms are recommended to use oral valganciclovir during the entire 6-month period. During antiviral drug treatment, absolute neutrophil count, platelet count, blood urea nitrogen, creatinine, and liver function tests were performed to identify neutropenia, thrombocytopenia, renal failure, and liver failure. This review investigated the evidence to date of treating congenital CMV infection.

Key words: Congenital, Cytomegalovirus infections, Ganciclovir, Valganciclovir, Sensorineural hearing loss

Key message

· Congenital cytomegalovirus (CMV) infection is among the most common causes of nongenetic sensorineural hearing loss.

· Congenital CMV is initially treated with intravenous ganciclovir for 2–6 weeks and switched to oral valganciclovir, or with oral valganciclovir for the entire 6-month period.

· Infants with congenital CMV require periodic monitoring of absolute neutrophil count, platelet count, and blood urea nitrogen, creatinine, liver function tests, audiological, ophthalmological, and developmental tests during antiviral medication.

Graphical abstract. Overview of the management of congenital cytomegalovirus infection. CMV, congenital cytomegalovirus; cCMV, congenital CMV; PCR, polymerase chain reaction; SNHL, sensorineural hearing loss; CBC, complete blood count; ANC, absolute neutrophil count; PC, platelet count; LFT, liver function test; AST, aspartate transaminase; ALT, alanine transaminase; TB, total bilirubin; DB, direct bilirubin; RFT, renal function test; BUN, blood urea nitrogen; VGCV, valganciclovir; BID, twice a day; IV, intravenous; GCV, ganciclovir.

Introduction

Human cytomegalovirus (CMV), which belongs to the Herpesviridae family and is the most common cause of congenital infection, has a prevalence of 0.2%–6%, even in developed countries [1]. Congenital CMV infection can cause neurodevelopmental disorders, such as cerebral palsy, intellectual disability, visual impairment, and seizures, and is the main cause of nonhereditary sensorineural hearing loss (SNHL) [2]. Antiviral treatment for congenital CMV infection began with ganciclovir 30 years ago, with oral valganciclovir being the most commonly used [3]. However, due to toxicity, these drugs should be used only when necessary after a thorough benefit–risk evaluation in infants with congenital CMV infection. Although treatment is essential for symptomatic infants with congenital CMV infection, that for infants with only isolated SNHL or asymptomatic disease is controversial [2]. This review aimed to examine studies of congenital CMV infection and determine when and how to treat infected patients.

Diagnosis and classification

Congenital CMV infection can be diagnosed by detecting CMV DNA in the newborn’s urine, saliva, or blood within 3 weeks of birth [3-11]. However, it cannot be diagnosed by the detection of CMV antibodies, nor can it be detected in samples collected more 3 weeks after birth because testing after this time cannot distinguish among congenital, perinatal, and postnatal infections [2,5,7].

Congenital CMV infection can be classified as moderately to severely symptomatic, mildly symptomatic, asymptomatic with isolates of SNHL, or asymptomatic. Moderately to severely symptomatic congenital CMV infection is defined as multiple manifestations (thrombocytopenia, petechiae, hepatomegaly, splenomegaly, intrauterine growth restriction, hepatitis) or central nervous system (CNS) involvement, such as microcephaly, radiographic abnormalities consistent with CMV CNS disease (ventriculomegaly, intracerebral calcifications, periventricular echogenicity, cortical or cerebellar malformations), abnormal cerebrospinal fluid indices for age, chorioretinitis, SNHL, or detection of CMV DNA in the cerebrospinal fluid. Mildly symptomatic congenital CMV infection is defined as infection with 1 or 2 isolated manifestations of congenital CMV infection, such as mild hepatomegaly, a single low platelet count measurement, or elevated alanine aminotransferase levels. Asymptomatic congenital CMV infection with isolated SNHL is defined as no apparent abnormalities suggestive of congenital CMV infection. Asymptomatic congenital CMV infection is defined as an infection with no apparent abnormalities suggestive of congenital CMV infection and normal hearing [5,12].

Target population of antiviral treatment

Whether antiviral treatment is required for infants with congenital CMV infection depends on the presence or absence of symptoms. Infants with congenital CMV infection who have significant symptoms, including significant end-organ diseases and CNS diseases, should receive immediate antiviral treatment [2,4,7,9,13]. However, antiviral treatment is not usually recommended in infants with mild symptoms (intrauterine growth retardation, liver enzyme elevation alone, or transient thrombocytopenia) or asymptomatic infants [4,7,9,14]. Tables 1–3 show the characteristics of previous prospective, retrospective, and randomized controlled trials [15-55].

Symptomatic infection

Antiviral treatment is recommended in infants with congenital CMV infection and end-organ symptoms in one or more organs or evidence of CNS involvement [4,14]. Treatment with intravenous ganciclovir and oral valganciclovir in infants with these symptoms improves long-term hearing and neurodevelopmental outcomes [22,33,53-55]. Kimberlin et al. conducted a randomized control study of 6 weeks of intravenous ganciclovir treatment and no treatment in 100 newborns with congenital CMV infection with CNS invasion that showed the ability of ganciclovir to reduce and prevent progressive SNHL [53]. In this study, a total of 43 patients underwent brainstem-evoked response at baseline and 1 year later, which worsened in five of 24 infants administered intravenous ganciclovir 1 year later and in 13 of 19 infants in the control (no treatment) group (P<0.01) [53]. Absolute neutrophil count (ANC) was measured in 89 patients; of them, 29 of 46 ganciclovir-administered patients and nine of 43 controls demonstrated grade 3–4 neutropenia (P<0.01) [53]. Oliver et al. [54] conducted Denver II neurodevelopmental tests at 6 weeks, 6 months, and 12 months and reported much lower rates of developmental delays at 6 and 12 months in the gancicloviradministered versus untreated control group. However, developmental delay was still noted in the ganciclovir-administered group versus the uninfected infants [54].

Asymptomatic infection with isolated hearing loss

Conflict persists regarding whether the benefits of antiviral treatment outweigh the risks in infants with isolated SNHL [4,56]. Completed clinical trials of antiviral treatment are lacking for this particular group. There is currently no clear evidence of the potential benefits of antiviral treatment in infants with SNHL isolates. Kimberlin et al. [55] reported recruiting patients with isolated SNHL, but only one was enrolled; therefore, it is not possible to determine the benefits of treating isolated SNHL in infants. Three multicenter clinical trials are underway in infants with isolated SNHL [57-59].

Asymptomatic infection with normal hearing

In a previous study, antiviral treatment in infants with asymptomatic congenital CMV infection showed no significant effects on hearing improvement [36,60]. Lackner et al. [36] conducted a small randomized study of 23 infants with asymptomatic congenital CMV infection with or without 3 weeks of ganciclovir treatment; among the final 18 infants, none of the 9 in the treatment group had delayed hearing loss versus 2 of nine in the untreated control group. Although the results of this study showed a positive effect in infants with asymptomatic congenital CMV infection, it is difficult to draw final conclusions from this study alone because of the small number of subjects. A phase 2 open clinical trial is currently underway to evaluate the therapeutic effect of oral valganciclovir in infants with asymptomatic congenital CMV infection [61].

Optimal timing and duration of antiviral treatment

In symptomatic infants, antiviral treatment should be initiated as soon as testing confirms a positive congenital CMV infection [62]. In previous clinical trials examining the effectiveness of antiviral therapy for congenital CMV infection, benefits were observed when treatment was initiated within the first 30 days of life [53,55]. Studies examining the benefits of starting treatment after 1 month of age showed some positive results [40,49]. A phase 2 randomized controlled study of the use of oral valganciclovir in infants and toddlers with congenital CMV infection and hearing loss between 1 month and 4 years of age is ongoing (NCT01649869) [59,63].

The current standard treatment period for infants with congenital CMV infection and symptoms is 6 months based on oral valganciclovir. A randomized controlled study by Kimberlin et al. [55] showed better hearing and neurodevelopmental prognosis in the oral valganciclovir 6-month use group; thereafter, oral valganciclovir 6-month treatment became the standard. However, infants with persistent viremia, retinitis, liver disease, and primary immune disorders may require oral valganciclovir therapy beyond 6 months of age. Infants with severe symptoms are monitored for CMV DNAemia, and antiviral treatment is administered if the viremia does not resolve after 6 months [62]. In a series of 23 infants treated with oral valganciclovir for 12 months, Amir et al. [37] found that long-term treatment was safe and associated with improved auditory outcomes compared with previous controls who received 6 weeks of treatment. In a retrospective study by Bilavsky et al. [43] of symptomatic infants with congenital CMV infection who started antiviral therapy during the first 4 weeks of life, receiving this treatment for 12 months with oral valganciclovir significantly improved hearing status. Therefore, further studies are needed to determine the optimal treatment period based on patient condition.

Initial evaluation before antiviral treatment

A comprehensive evaluation of infected newborns is required before antiviral treatment is initiated [4,9,14,62]. A thorough physical examination is necessary to detect the symptoms and signs of congenital CMV infection. Baseline levels were confirmed using tests such as ANC and platelet count. A renal function test that checks the baseline levels of blood urea nitrogen and blood creatinine is used to determine whether a dose adjustment of the antiviral drug is necessary. Hepatic transaminase, total bilirubin, and direct bilirubin levels confirmed the baseline liver function test results. Neuroimaging using brain ultrasound, computed tomography of the brain, or magnetic resonance imaging of the brain is required to evaluate the extent of CNS involvement. A hearing test and ophthalmic examination are also required for the baseline setup. A CMV DNAemia test using quantitative polymerase chain reaction (PCR) is required to confirm the degree of viremia (Fig. 1).

Antiviral agents

Intravenous ganciclovir or its oral prodrug valganciclovir is currently used to treat congenital CMV infection. Antiviral drugs inhibit CMV replication by interfering with viral DNA synthesis. Pharmacokinetic studies have shown that oral valganciclovir has similar efficacy to intravenous ganciclovir [19]. The use of intravenous ganciclovir is only recommended in cases in which enteral supply is difficult; once enteral intake is established, treatment should be changed to oral valganciclovir, which features fewer side effects [7]. Foscarnet and cidofovir are used in cases of refractory CMV infection, ganciclovir resistance, ganciclovir toxicity, and coinfection with adenovirus [64-66].

1. Ganciclovir

Whitley et al. [17] conducted a phase 2 clinical trial comparing ganciclovir treatment 12 mg/kg/day and 8 mg/kg/day for 6 weeks in infants with congenital CMV infection; the former group showed better hearing improvement. After this study, ganciclovir 6 mg/kg/dose was administered intravenously twice a day to treat congenital CMV infection [17,37,53,54,67]. Subsequently, improved hearing outcomes and neurodevelopmental sequelae were reported with intravenous ganciclovir treatment between 6 months and 1 year in a phase 3 study of symptomatic infants with congenital CMV infection with neurological involvement [53,54]. Ganciclovir effectively treated congenital CMV infection, but it was not widely used because it required long-term intravenous infusions with serious adverse effects. Accordingly, Kimberlin et al. [19] evaluated the pharmacokinetics of valganciclovir, an oral ganciclovir formulation, and found that administration of 16 mg/kg/dose twice a day reached the same blood concentration as intravenous ganciclovir. In addition, the use of oral valganciclovir reduced the risk of neutrophil reduction compared to the use of intravenous ganciclovir, and the gonadotoxicity and carcinogenicity induced by ganciclovir were not observed with oral valganciclovir. Thereafter, oral valganciclovir became the treatment of choice for congenital CMV infections. Subsequently, Kimberlin et al. [55] conducted a randomized controlled trial comparing oral valganciclovir for 6 months and 6 weeks in 96 infants with symptomatic congenital CMV infections regardless of CNS involvement; the 6-month group showed better hearing improvement (or even normal hearing) at 24 months compared to the 6-week group (67% vs. 64%, P=0.045) as well as higher language (P=0.004) and receptive communication scores (P=0.003) at 24 months. Many other studies provided evidence that ganciclovir treatment may improve hearing and neurologic outcomes in infants with symptomatic congenital CMV infection [15,16,18,21,22,24,27-47,49,52]. Ganciclovir should be administered via a central venous catheter when possible. If short ganciclovir treatment (<2 weeks) is anticipated, a well-functioning peripheral intravenous catheter can be used for dosing if the intravenous site is carefully monitored during the infusion [3,62].

2. Valganciclovir

In 3 case studies, oral valganciclovir improved or preserved the hearing of infants with symptomatic congenital CMV infection [20,23,40]. The Collaborative Antiviral Study Group conducted a phase 1/2 pharmacokinetic/pharmacodynamic study of oral valganciclovir in neonates with congenital CMV infection with or without CNS involvement in 2002–2007 showed that oral administration at a dose of 16 mg/kg/dose twice daily produced ganciclovir blood levels similar to those with intravenous administration at a dose of 6 mg/kg/dose every 12 hours [19]. In a subsequent randomized control trial by Kimberlin et al., valgancilcovir was administered orally at a dose of 16 mg/kg twice daily; this dosage is currently recommended [2,55,62].

Infants receiving intravenous ganciclovir should also be switched to oral valganciclovir within 2–6 weeks if they are clinically stable and can take oral medications. After switching to oral valganciclovir, treatment should be continued for 6 months.

3. Others

Foscarnet and cidofovir are not routinely used to treat congenital CMV infections, and data on their use in these settings are limited [64-66]. These agents may be used in some cases in which ganciclovir resistance is suspected or confirmed or when severe toxicity occurs during treatment with intravenous ganciclovir or oral valganciclovir.

Supportive management

In some cases of congenital CMV infection, symptoms such as sepsis-like illness, myocarditis, viral-induced hemophagocytic lymphohistiocytosis, or severe neurological involvement may be present. In infants with these symptoms, supportive management is important in addition to antiviral treatment. Supportive management includes fluid therapy, blood transfusions, blood pressure control, seizure control, respiratory support, adequate nutrition, and antibiotic treatment of secondary bacterial infections [3,6,62,68].

Adverse effects of antiviral treatment

1. Neutropenia

Neutropenia is known to occur in 25%–60% of neonates treated with intravenous ganciclovir and about 20% of infants treated with oral valganciclovir [53-55,69,70]. Severe cases are rare and usually resolve by stopping antiviral drugs for 1–7 days and re-administering the same dose once the ANC has recovered. Treatment may require discontinuation if the neutropenia recurs [62].

2. Thrombocytopenia

Thrombocytopenia (platelet count <50,000 cells/µL) reportedly occurs in 6% of infants during intravenous ganciclovir therapy [69,71]. However, infants with congenital CMV infection often have low platelet counts at birth; thus, the relative contribution of ganciclovir to the thrombocytopenia is unclear. In a randomized controlled trial, thrombocytopenia occurred at similar rates in infants treated with intravenous ganciclovir and in untreated infants (7% vs. 5%, respectively) [53].

3. Renal toxicity

Elevated serum creatinine levels reportedly occur in less than 1% of infants treated with intravenous ganciclovir and oral valganciclovir [69,71]. Doses of intravenous ganciclovir and oral valganciclovir should be adjusted in infants with renal failure [62].

4. Hepatotoxicity

Hepatotoxicity was observed in infants receiving intravenous ganciclovir, especially at a dose of 6 mg/kg or higher [69,71]. A slight elevation of aminotransferase (<100 IU/L) is particularly common in infants receiving oral valganciclovir, which is generally not a problem [62].

5. Problems associated with intravenous catheters

Problems with intravenous catheters are common during ganciclovir treatment. The extravasation of intravenous ganciclovir may cause local reactions, ulcers, and scars. Therefore, intravenous ganciclovir should be administered through a central venous catheter; if oral administration is possible, the switch to oral valganciclovir should be quickly made [33,53,62].

Long-term effects

Animal studies have shown that intravenous ganciclovir or oral valganciclovir may involve reversible testicular damage, reduced sperm viability, and carcinogenic effects [64,71-73], but this has not been shown in human studies.

Monitoring

In cases of intravenous ganciclovir or oral valganciclovir for the treatment of congenital CMV infections, periodic blood tests are required to check for toxicity. Checks for ANC and platelet counts are required to confirm neutropenia or thrombocytopenia. Liver function tests (aspartate aminotransferase, alanine aminotransferase, and total and direct bilirubin levels) and renal function tests (blood urea nitrogen and creatinine levels) should be additionally performed [14]. ANC and platelet counts should be determined weekly for 6 weeks, then at 8 weeks, and then monthly during the treatment period [19,55]. Monthly liver and kidney function tests are also recommended [19,55]. Quantitative CMV DNA PCR measurements of whole blood or plasma to determine the degree of viral load can be performed to determine the effectiveness of antiviral treatment [3,62,74]. Some studies have shown a correlation between a low viral load and improved hearing outcomes [55,74]. Infants treated for congenital CMV infection should undergo regular hearing examinations up to 6 years of age and followed up with ophthalmic examinations until 5 years of age [7].

Problems requiring solving

A number of problems in the treatment of congenital CMV infections require solving [3,7,9]. In infants with congenital CMV infection, it is necessary to determine whether there is any benefit in starting treatment after 30 days of age. It is necessary to determine whether there is any benefit to treating mild or asymptomatic children, and a comparative study examined 6- and 12-month treatment with oral valganciclovir [35]. As with most drug therapies, studies of the safety and efficacy of antiviral drugs used for treating congenital CMV infection in preterm infants are limited. All clinical trials establishing the pharmacokinetics, safety, and efficacy of intravenous ganciclovir versus oral valganciclovir were limited to infants born at ≥32 weeks’ gestation at a birth weight of ≥1,200 g. Although there are several case studies on the effective use of intravenous ganciclovir and oral valganciclovir in preterm infants aged <32 weeks’ gestation, clinical studies on antiviral treatment are lacking [13,35,75-79]. Further clinical studies are needed to establish a treatment for congenital CMV infection in preterm infants.

Ongoing trials

Various institutions are currently conducting studies on treating congenital CMV infections. The Collaborative Antiviral Study Group is conducting a phase 2 randomized controlled trial of oral valganciclovir therapy in children up to 4 years of age with congenital CMV infection and SNHL isolates (NCT 01649869) [58]. A nonrandomized single-blind clinical trial is investigating whether early treatment with oral valganciclovir up to 12 weeks of age in congenital CMV infection with SNHL may prevent the progression of hearing loss (NCT02005822) [59]. In addition, a clinical trial of whether oral valganciclovir for 6 months can prevent hearing loss in children with isolated SNHL has been completed, and the results are currently being analyzed (NCT03107871). Another clinical trial of whether oral valganciclovir treatment for 6 months can prevent hearing loss in children with isolated SNHL has also been completed and is under analysis (NCT03107871) [57]. The National Institute of Allergy and Infectious Diseases is conducting a phase 2 clinical trial of oral valganciclovir administration in asymptomatic infants (NCT03301415) [61].

Conclusions

Congenital CMV infection is a major cause of nonhereditary SNHL that can lead to neurodevelopmental disorders in the brain. Infants with symptomatic congenital CMV infection may benefit from hearing and neurodevelopmental prognoses, especially if antiviral therapy is initiated within the first month of life. The currently recommended drug regimen for symptomatic infants with congenital CMV infection is as follows: infants with life-threatening symptoms are initially treated with intravenous ganciclovir for 2–6 weeks and then switched to oral valganciclovir, while those without life-threatening symptoms are treated with oral valganciclovir for the entire 6-month period. Monitoring of ANC, platelet count, blood urea nitrogen, creatinine, and liver function tests is required to identify neutropenia, thrombocytopenia, renal failure, and liver failure during antiviral treatment. However, additional studies are needed of the treatment of preterm infants born at <32 weeks’ gestation, starting in those older than 1 month of age, of those with isolated SNHL, and of asymptomatic infants.

Footnotes

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Fig. 1.

Schematic diagram of treatment and monitoring of infants diagnosed with congenital CMV infection. CMV, cytomegalovirus; PCR, polymerase chain reaction; SNHL, sensory neural hearing loss; FU, follow-up; VGCV, valganciclovir; BID, twice a day; IV, intravenous; GCV; ganciclovir; CBC, complete blood count; ANC, absolute neutrophil count; LFT, liver function test; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TB, total bilirubin; DB, direct bilirubin; RFT, renal function test; BUN, blood urea nitrogen; Cr, creatinine.

Table 1.

Prospective clinical studies of antiviral treatment of cCMV infection

Study	Design and population	Control	Intervention	Results
Trang et al., 1993 [15]	Open phase I–II pharmacokinetic, safety, and tolerance trial, symp tomatic cCMV infection, 2 to 49 days,		IV ganciclovir, single dose of either 4 mg/kg (n=14) or 6 mg/ kg (n=13)	No significant differences between the 2 dose groups
Zhou et al., 1996 [16]	Open phase I–II pharmacokinetic, safety, and tolerance trial, sympto matic cCMV infection, newborns		IV ganciclovir, single dose of either 4 mg/kg (n=14) or 6 mg/ kg (n=13)	No significant differences between the 2 dose groups, no significant adverse effect
Whitley et al., 1997 [17]	Phase II trial, symptomatic cCMV infection, 2–30 days		IV ganciclovir, 8 mg/kg (n=14) or 12 mg/kg (n=28) q 12 hr for 6 wk	Hearing improvement or stabilization at 6 months or later (5 of 30, 16%)
Acosta et al., 2007 [18]	Phase I–II pharmacokinetic trial, symptomatic cCMV infection, 8–34 days		IV ganciclovir (6mg/kg q 12 hr) or oral valganciclovir (14 mg/kg BID) for 6 wk (n=24)	Similar clearance, distribution volume, and bioavailability
Kimberlin et al., 2008 [19]	Phase I–II pharmacokinetic and pharmacodynamic trial, symp tomatic cCMV infection. 6–31 days		IV ganciclovir (6mg/kg q 12 hr) or oral valganciclovir (14 mg/kg BID) for 6 wk (n=24)	The bioavailability of valganciclovir, 41.1%; subjects with the higher viral burden experi enced greater decreases; neutropenia of grade 3 or 4 (9 of 24, 38%)
Lombardi et al, 2009 [20]	Pharmacokinetics trial, symptomatic cCMV infection, newborns		Oral valganciclovir, 15 mg/kg BID for 6 wk (n=13)	Stable and effective plasma concentrations; at the 6month followup no patients had worsened, 2 had improved; few adverse effects
Foulon et al., 2012 [21]	Prospective cohort study, sympto matic cCMV infection and isolated HL newborns		IV ganciclovir, 6mg/kg q 12 hr for 6 wk (n=6/62)	Unstable hearing 29.4%; fluctuations 16.2%; lateonset HL 4.3% of children with a normal hearing at birth
Royackers et al., 2013 [22]	Prospective cohort study, cCMV infection, newborns	Nine symptomatic and 11 asymptomatic children did not receive ganciclovir	IV ganciclovir, 6mg/kg q 12 hr for 6 wk (n=8)	Treated group, stable HL 37.5%, progressive and/or fluctuating HL, 37.5%; untreated group, stable HL 33.3%, progression or fluctuation HL occurred in 55.5%
Nishida et al., 2016 [23]	Prospective cohort study, symp tomatic cCMV infection, 4–77 days		Oral valganciclovir (16–32 mg/kg/ day) for 6 wk and IV immuno globulin (300 mg/kg/dose) twice within 2 wk (n=12)	Severe impairment (4, 33%), mild impairment (3, 25%), normal (5, 42%)
Dong et al., 2018 [24]	Pharmacokinetic study, sympto matic cCMV infection, 3–70 days		IV ganciclovir, 5 mg/kg q 12 hr (n=26)	All adapted AUC0–24 values achieved the target.
Ohyama et al., 2019 [25]	Prospective cohort study, symp tomatic cCMV infection, 4–105 days		Oral valganciclovir (32 mg/kg/ day) for 6 wk (n=20) or 6 mo (n=6)	Of 52 ears in 26 infants with cCMV infection, 29 (56%) had hearing dysfunction, and of 29 ears, 16 (55%) improved after treatment. Although, 16 (84%) of 19 ears with mode rate or severe hearing dysfunction improved after treatment (P<0.001), 10 ears with the most severe form did not.
Morioka et al., 2022 [26]	A multicenter, singlearm, open label clinical trial, symptomatic cCMV infection with CNS involvement, 14–66 days		Oral valganciclovir, 16 mg/kg BID for 6 mo (n=25), younger age group (14–28 days) vs older age group (31–66 days)	No differences in hearing efficacy between the 2 groups

cCMV, congenital cytomegalovirus; BID, twice a day; HL, hearing loss; IV, intravenous; SNHL, sensorineural hearing loss; AUC, area under curve; CNS, central nervous system.

Table 2.

Retrospective cohort and case studies of antiviral treatment of cCMV infection

Study	Design and population	Control	Intervention	Results
Hocker et al., 1990 [27]	Case study. symptomatic cCMV infection		IV ganciclovir, 5 mg/kg q 12 hr for 4 wk	Expired
Nigro et al., 1994 [28]	Retrospective cohort study, symptomatic cCMV infection, 14 days to 6 mo	IV ganciclovir IV, 5 mg/kg q 12 h for 2 wk (group 1, n=6)	IV ganciclovir, 7.5 mg/kg q 12 hr for 2 wk and 10 mg/kg 3 times weekly for 3 mo (group 2, n=6)	No differences between 2 groups
Vallejo et al., 1994 [29]	Case study. symptomatic cCMV infection		IV ganciclovir, 6 mg/kg QD for 3 wk	Clinical improvement, normal de velopment at 9 mo
Min et al., 1996 [30]	Case study, cCMV pneumonitis		IV ganciclovir, 510 mg/kg, 10 wk	Clinical improvement
Jang et al., 2001 [31]	Case study, symptomatic CMV infection with HL		IV ganciclovir 10 mg/kg/day for 2 wk, then 6 mg/kg/day for 4 wk	Clinical improvement
Yang et al., 2003 [32]	Case study, cCMV colitis		IV ganciclovir for 3 wk	Clinical improvement
Michaels et al., 2003 [33]	Retrospective cohort study, symptomatic cCMV infection, 7 days to 11 mo		IV ganciclovir (10 mg/kg/day), decreased to 5 mg/kg/day after 2 to 4 wk and administered for a median of 12 mo (range, 5.5 to 18 mo); subsequent to oral valganciclovir admini stered 550 mg/m²/dose TID for a median of 10 mo (range, 6 mo to 3 yr)	No child had progression of HL, im provement occurred in 2; central venous catheter/site infection (n= 6), catheter malfunction (n=3), neu tropenia (n=1).
Tanaka Kitajima et al., 2005 [34]	Case series, symptomatic cCMV infection, 0–45 days		IV ganciclovir, 5–12 mg/kg/day for 2–7 wk	Clinical findings did not always wor sen; improvement of HL (n=2)
Müller et al., 2008 [35]	Case study, symptomatic cCMV infection		IV ganciclovir, 5 mg/kg q 12 hr for 32 days and continued with oral valganciclovir for further 6 wk	Clinical signs resolved and virus load decreased slowly during treatment. At discharge BSEA was normal.
Lackner et al., 2009 [36]	Retrospective cohort study, symptomatic cCMV infection	No treatment (n=11)	IV ganciclovir10 mg/kg/day for 21 days (n=12)	SNHL (n=2) in no treatment group
Amir et al., 2010 [37]	Retrospective cohort study, symptomatic cCMV infection, newborns	Ganciclovir for 6 wk only (historical control)	IV ganciclovir for 6 wk followed by oral valganciclovir to age 12 mo (n=23)	Significantly better auditory outcome than reported in a historical control (P=0.001)
Lee et al., 2012 [38]	Case study, symptomatic cCMV with HL		IV ganciclovir 30–35 mg for 6 wk	Hearing improvement
Kim et al., 2012 [39]	Case study, symptomatic cCMV with PH		IV ganciclovir for 6wks (n=2)	Clinical improvement
del Rosal et al., 2012 [40]	Retrospective case series study, symptomatic cCMV infection and CNS involve ment, 1.8–8.8 mo		Oral valganciclovir 32 mg/kg/days or IV ganciclovir prior to valganciclovir at 12 mg/ kg/days during 3.5–12 mo (n=13)	At 12 mo, 9 remained stable, 7 had improved and none had worsened; in 8 normal ears at baseline, no deterioration at 12 mo
Amir et al., 2014 [41]	Retrospective cohort study, cCMV infection with late onset HL, 4–34 mo		Two protocols:	BSEA testing revealed HL in 35 of 42 ears (83%). Hearing thresholds improved in 29 ears (69%). None of the patients needed a cochlear implant.
			(1) IV ganciclovir (5 mg/kg/d for 6 wk) → oral valganciclovir (17 mg/kg/dose BID for 6 wk → QD until 1 yr
			(2) oral valganciclovir (17 mg/kg/dose BID → QD for 9 mo) (n=21)
Bilavsky et al., 2015 [42]	Retrospective cohort study, symptomatic cCMV infection, newborns	Group 1: infants with no hearing impairment at birth & not treated during 2006–2009 (n=13)	Group 2: infants with LSV and no hearing im pairment & treated since mid2009 (n= 51)	More extensive hearing deterioration in group 1 (85%) than in group 2 (0%, P <0.001) and the asympto matic group (10%, P<0.001); hear ing deterioration more often in group 4 (10%) than in group 2 (0%, P=0.008)
			Group 3: infants born with LSV, HL, & treated since mid2009 (n=25)
		Group 4: control infants born since mid-2009 with asymptomatic cCMV (n= 52)	Two protocols:
			(1) IV ganciclovir (5 mg/kg/days for 6 wk) → oral valganciclovir (17 mg/kg/dose BID for 6 wk → QD until 1 yr
			(2) oral valganciclovir (17 mg/kg/dose BID → QD for 9 mo)
Bilavsky et al., 2016 [43]	Retrospective cohort study, symptomatic cCMV infection, first 4 weeks of life		Two protocols:	1Year FU 77 affected ears at base line, 50 (64.9%) had improved, 22 (28.6%) remained unchanged and 5 (6.5%) had deteriorated; most improved ears returned to normal hearing (38 of 50, 76%)
			(1) IV ganciclovir (5 mg/kg/days for 6 wk) → oral valganciclovir (17 mg/kg/dose BID for 6 wk → QD until 1 yr
			(2) oral valganciclovir (17 mg/kg/dose BID → QD for 9 mo) (n=149)
Kim et al., 2017 [44]	Case study, symptomatic cCMV infection in discordant twin		IV ganciclovir 6 wk+3 wk, then oral valganciclovir for 7 wk	No improvement
Mazzaferri et al., 2017 [45]	Retrospective cohort study, cCMV infection with isolated HL, within the first 10 days of life		IV ganciclovir (6 mg/kg q 12 hr) or oral valganciclovir (16 mg/kg BID) within the first 10 DOLs for 6 wk (n=13)	Hearing improvement between baseline and 2yr FU (P=0.0163)
Pasternak et al., 2018 [46]	Retrospective cohort study, cCMV infection with isolated HL, within the first 12 wk of life		Two protocols:	Of the 80 affected ears at baseline, 55 (68.8%) improved, and only 2 (2.5%) deteriorated. Most of the improved ears (53 of 55, 96.3%) returned to normal hearing.
			(1) IV ganciclovir (5 mg/kg/days for 6 wk) → oral valganciclovir (17 mg/kg/ dose BID for 6 wk → QD until 1 yr
			(2) oral valganciclovir (17 mg/kg/dose BID → QD for 9 mo) (n=59)
Koyano et al., 2018 [47]	Retrospective cohort study, symptomatic cCMV infection and isolated HL, newborns		IV ganciclovir (6 mg/kg q 12 hr) or oral valganciclovir (16 mg/kg BID) for 6 wk (n=10)	All 7 symptomatic infants without treatment developed sequelae; 3 of the 10 treated patients free from any sequelae
McCrary et al., 2019 [48]	Retrospective cohort study, symptomatic cCMV infection, <1 mo (n=8) and >1 mo (n=8)		Oral valganciclovir at a dose of 16 mg/ kg BID for 6 wk or 6 mo (n=16)	14 of 16 patients (87.5%, P <0.001) were found to have clinically signifi cant worsening of hearing.
Dorfman et al., 2020 [49]	Retrospective cohort study, symptomatic cCMV infection and lateonset HL, 12–156 wk		Two protocols:	Symptomatic group: 45 affected ears, 30 (66.7%) improved and only 2 (4.4 %) deteriorated; asymptomatic group: out of the 42 deteriorated ears, 38 (90.5%) improved after at least 1yr FU
			(1) IV ganciclovir (5 mg/kg/days for 6 wk) → oral valganciclovir (17 mg/kg/ dose BID for 6 wk → QD until 1 yr
			(2) oral valganciclovir (17 mg/kg/dose BID → QD for 9 mo) (n=91)
Turriziani Colonna et al., 2020 [50]	Retrospective cohort study, cCMV infection, within first month of life		Oral valganciclovir 16 mg/kg/dose BID, for a variable number of 6wk cycles	Abnormal cognitive assessment scales, 4/35 patients (11.4%); abnormal scores in neuropsychological tests, 11 of 21 patients (52.4%); pathological language evaluation scores, 6 of 21 patients (28.5%); developed SNHL, 6 of 35 patients (17.1%)
Suganuma et al., 2021 [51]	Retrospective cohort study, cCMV infection, 0–46 mo		Oral valganciclovir 14–15 mg/kg BID, increased to 16 mg/kg BID one week after confirming no ADEs (n= 26)	21 Patients (81%) had SNHL at base line: 5 patients (19%) presented with improved SNHL, none experienced worsened SNHL during treatment
Lanzieri et al., 2022 [52]	Retrospective cohort study, symptomatic cCMV infection, 0–46 mo	Group B untreated who symptomatic cCMV with microcephaly, chorioretinitis, or SNHL (≥25 dB) (n=27)	Group A who treated with IV gan ciclovir for 6 wk who symptomatic cCMV (n=17)	By the end of FU, 12 (71%), 16 (59%), and 7 (22%) of patients in groups A, B, and C, respectively, had severe (>70 dB) SNHL in the better hearing ear.
Lanzieri et al., 2022 [52]		Group C untreated who did not meet criteria for group B (n= 32)

cCMV, congenital cytomegalovirus; IV, intravenous; QD, once a day; HL, hearing loss; TID, 3 times a day; BSEA, brain stem-evoked audiometry; SNHL, sensorineural hearing loss; PH, pulmonary hypertension; CNS, central nervous system; BID, twice a day; LSV, lenticulostriated vasculopathy; FU, follow-up; DOL, day of life; ADE, adverse effect.

Table 3.

Randomized controlled trials of antiviral treatment of cCMV infection

Study	Design and population	Control	Intervention	Results
Kimberlin et al., 2003 [53]	RCT, symptomatic cCMV infection involving the CNS, 3 days to 11 mo	No treatment (n=17)	IV ganciclovir, 6 mg/kg q 12 hr for 6 wk (n=25)	No child had progression of hearing loss; improvement occurred in 2.
Oliver et al, 2009 [54]	RCT, symptomatic cCMV infection involving the CNS, 333 days	No treatment (n=36)	IV ganciclovir, 6 mg/kg q 12 hr for 6 wk (n=35)	In a multivariate regression model, the effect of ganciclovir therapy remained statistically significant at 12 mo (P = 0.007).
Kimberlin et al., 2015 [55]	RCT, symptomatic cCMV infection, newborns	Oral valganciclovir at a dose of 16 mg/kg BID for 6 wk only (n=49)	Oral valganciclovir at a dose of 16 mg/kg BID for 6 mo (n=47)	Totalear hearing was more likely to be improved or to remain normal at 12 mo in the 6mo group than in the 6wk group (73% vs. 57%, P=0.01). Better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, 3rd ed., on the languagecomposite component (P=0.004) and on the receptive communication scale (P=0.003).

cCMV, congenital cytomegalovirus; RCT, randomized controlled trial; CNS, central nervous system; BID, twice a day.

References

1. Kalser J, Adler B, Mach M, Kropff B, Puchhammer-Stöckl E, Görzer I. Differences in growth properties among two human cytomegalovirus glycoprotein O genotypes. Front Microbiol 2017;8:1609.

2. Weimer KE, Permar SR. When and how to treat neonatal CMV infection. In: Benitz WE, Smith PB, editors. Infectious disease and pharmacology. Philadelphia (PA): Elsevier, 2019:27-36.

3. Chiopris G, Veronese P, Cusenza F, Procaccianti M, Perrone S, Daccò V, et al. Congenital cytomegalovirus infection: update on diagnosis and treatment. Microorgan 2020;8:1516.

4. Luck SE, Wieringa JW, Blázquez-Gamero D, Henneke P, Schuster K, Butler K, et al. Congenital cytomegalovirus: a European expert consensus statement on diagnosis and management. Pediatr Infect Dis J 2017;36:1205–13.

5. Rawlinson WD, Boppana SB, Fowler KB, Kimberlin DW, Lazzarotto T, Alain S, et al. Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect Dis 2017;17:e177–88.

6. Marsico C, Kimberlin DW. Congenital cytomegalovirus infection: advances and challenges in diagnosis, prevention and treatment. Ital J Pediatr 2017;43:1–8.

7. Lim Y, Lyall H. Congenital cytomegalovirus–who, when, what-with and why to treat? J Infect 2017;74 Suppl 1:S89–94.

8. Pesch MH, Kuboushek K, McKee MM, Thorne MC, Weinberg JB. Congenital cytomegalovirus infection. BMJ 2021;373:n1212.

9. Jenks CM, Hoff SR, Mithal LB. Congenital cytomegalovirus infection: epidemiology, timely diagnosis, and management. NeoReviews 2021;22:e606–13.

10. Lazzarotto T, Blázquez-Gamero D, Delforge M-L, Foulon I, Luck S, Modrow S, et al. Congenital cytomegalovirus infection: a narrative review of the issues in screening and management from a panel of European experts. Front Pediatr 2020;8:13.

11. Kabani N, Ross SA. Congenital cytomegalovirus infection. J Infect Dis 2020;221(Suppl 1): S9–14.

12. Annelies K, Leenheer D, Alexandra C, Veerle C, Sabine L, Ludo M, et al. Results of a multicenter registry for congenital cytomegalovirus infection in Flanders, Belgium: from prenatal diagnosis over neonatal management to therapy. Early Hum Dev 2021;163:105499.

13. Kimberlin DW BE, Lynfield R, Sawyer MH. Red Book: 2021-2024 report of the Committee on Infectious Diseases (32nd edition). Elk Grove Village (IL): American Academy of Pediatrics, 2021.

14. Kimberlin D, Brady M, Jackson M, Long S, Pediatrics AAo. Cytomegalovirus infection. Red Book 2018 Report of the Committee on Infectious Diseases (31st edition). Elk Grove Village (IL): American Academy of Pediatrics, 2018:320.

15. Trang JM, Kidd L, Gruber W, Storch G, Demmler G, Jacobs R, et al. Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. Clin Pharmacol Therapeut 1993;53:15–21.

16. Zhou XJ, Gruber W, Demmler G, Jacobs R, Reuman P, Adler S, et al. Population pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group. Antimicrob Agents Chemother 1996;40:2202–5.

17. Whitley RJ, Cloud G, Gruber W, Storch GA, Demmler GJ, Jacobs RF, et al. Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. J Infect Dis 1997;175:1080–6.

18. Acosta EP, Brundage RC, King JR, Sánchez PJ, Sood S, Agrawal V, et al. Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation. Clin Pharmacol Ther 2007;81:867–72.

19. Kimberlin DW, Acosta EP, Sánchez PJ, Sood S, Agrawal V, Homans J, et al. Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease. J Infect Dis 2008;197:836–45.

20. Lombardi G, Garofoli F, Villani P, Tizzoni M, Angelini M, Cusato M, et al. Oral valganciclovir treatment in newborns with symptomatic congenital cytomegalovirus infection. Eur J Clin Microbiol Infect Dis 2009;28:1465–70.

21. Foulon I, Naessens A, Faron G, Foulon W, Jansen AC, Gordts F. Hearing thresholds in children with a congenital CMV infection: a prospective study. Int J Pediatr Otorhinolaryngol 2012;76:712–7.

22. Royackers L, Rector E, Verhaert N, Desloovere C. Long-term audiological follow-up of children with congenital cytomegalovirus. B-ENT 2013;Suppl 21:57–64.

23. Nishida K, Morioka I, Nakamachi Y, Kobayashi Y, Imanishi T, Kawano S, et al. Neurological outcomes in symptomatic congenital cytomegalovirusinfected infants after introduction of newborn urine screening and antiviral treatment. Brain Dev 2016;38:209–16.

24. Dong Q, Leroux S, Shi HY, Xu HY, Kou C, Khan MW, et al. Pilot study of model-based dosage individualization of ganciclovir in neonates and young infants with congenital cytomegalovirus infection. Antimicrob Agents Chemother 2018;62:e00075–18.

25. Ohyama S, Morioka I, Fukushima S, Yamana K, Nishida K, Iwatani S, et al. Efficacy of valganciclovir treatment depends on the severity of hearing dysfunction in symptomatic infants with congenital cytomegalovirus infection. Int J Molec Sci 2019;20:1388.

26. Morioka I, Kakei Y, Omori T, Nozu K, Fujioka K, Takahashi N, et al. Oral valganciclovir therapy in infants aged ≤ 2 months with congenital cytomegalovirus disease: a multicenter, single-arm, open-label clinical trial in Japan. J Clin Med 2022;11:3582.

27. Hocker JR, Cook LN, Adams G, Rabalais GP. Ganciclovir therapy of congenital cytomegalovirus pneumonia. Pediatr Infect Dis J 1990;9:743–4.

28. Nigro G, Scholz H, Bartmann U. Ganciclovir therapy for symptomatic congenital cytomegalovirus infection in infants: a two-regimen experience. J Pediatr 1994;124:318–22.

29. Vallejo JG, Englund JA, Garcia-Prats JA. Ganciclovir treatment of steroid-associated cytomegalovirus disease in a congenitally infected neonate. Pediatr Infect Dis J 1994;13:239–40.

30. Min JY, Hong SJ, Moon HN, Hong CY. A case report: ganciclovir therapy of cytomegalovirus pneumonitis. J Korean Pediatr Soc 1996;39:142–7.

31. Jang SJ, Cho YJ, Lee SL, Kim JS, Kwon TC. A neonatal case of symptomatic congenital cytomegalovirus infection with hearing defect. J Korean Pediatr Soc 2001;44:205–10.

32. Yang HR, Kim YJ, Seo JK, Kim WS, Gang GH, Park KW. A case of congenital cytomegalovirus colitis with colonic stricture. Korean J Pediatr Gastroenterol Nutr 2003;6:59–67.

33. Michaels MG, Greenberg DP, Sabo DL, Wald ER. Treatment of children with congenital cytomegalovirus infection with ganciclovir. Pediatr Infect Dis J 2003;22:504–8.

34. Tanaka-Kitajima N, Sugaya N, Futatani T, Kanegane H, Suzuki C, Oshiro M, et al. Ganciclovir therapy for congenital cytomegalovirus infection in six infants. Pediatr Infect Dis J 2005;24:782–5.

35. Müller A, Eis-Hübinger A, Brandhorst G, Heep A, Bartmann P, Franz A. Oral valganciclovir for symptomatic congenital cytomegalovirus infection in an extremely low birth weight infant. J Perinatol 2008;28:74–6.

36. Lackner A, Acham A, Alborno T, Moser M, Engele H, Raggam R, et al. Effect on hearing of ganciclovir therapy for asymptomatic congenital cytomegalovirus infection: four to 10 year follow up. J Laryngol Otol 2009;123:391–6.

37. Amir J, Wolf DG, Levy I. Treatment of symptomatic congenital cytomegalovirus infection with intravenous ganciclovir followed by longterm oral valganciclovir. Eur J Pediatr 2010;169:1061–7.

38. Lee DY, Park SH, Cha TK, Yoo JC. A case of hearing improvement in congenital cytomegalovirus infected infant with sensorineural hearing loss. Korean J Otorhinolaryngol Head Neck Surg 2012;55:582–5.

39. Kim AY, Kim YS, Park KH, Byun SY. Two cases of congenital cytomegalovirus infection with pulmonary hypertension. Korean J Perinatol 2012;23:273–9.

40. del Rosal T, Baquero-Artigao F, Blázquez D, Noguera-Julian A, Moreno-Pérez D, Reyes A, et al. Treatment of symptomatic congenital cytomegalovirus infection beyond the neonatal period. J Clin Virol 2012;55:72–4.

41. Amir J, Attias J, Pardo J. Treatment of late-onset hearing loss in infants with congenital cytomegalovirus infection. Clin Pediatr (Phila) 2014;53:444–8.

42. Bilavsky E, Schwarz M, Pardo J, Attias J, Levy I, Haimi-Cohen Y, et al. Lenticulostriated vasculopathy is a high-risk marker for hearing loss in congenital cytomegalovirus infections. Acta Paediatr 2015;104:e388–94.

43. Bilavsky E, Shahar-Nissan K, Pardo J, Attias J, Amir J. Hearing outcome of infants with congenital cytomegalovirus and hearing impairment. Arch Dis Child 2016;101:433–8.

44. Kim YS, Kang JM, Lee JH, Chang YS, Park WS, Kim YJ. Discordant congenital cytomegalovirus infection in twins. Pediatr Infect Vaccine 2017;24:65–70.

45. Mazzaferri F, Cordioli M, Conti M, Storato S, Be G, Biban P, et al. Symptomatic congenital cytomegalovirus deafness: the impact of a six0week course of antiviral treatment on hearing improvement. Infez Med 2017;25:347–50.

46. Pasternak Y, Ziv L, Attias J, Amir J, Bilavsky E. Valganciclovir is beneficial in children with congenital cytomegalovirus and isolated hearing loss. J Pediatr 2018;199:166–70.

47. Koyano S, Morioka I, Oka A, Moriuchi H, Asano K, Ito Y, et al. Congenital cytomegalovirus in Japan: more than 2 year follow up of infected newborns. Pediatr Int 2018;60:57–62.

48. McCrary H, Sheng X, Greene T, Park A. Long-term hearing outcomes of children with symptomatic congenital CMV treated with valganciclovir. Int J Pediatr Otorhinolaryngol 2019;118:124–7.

49. Dorfman L, Amir J, Attias J, Bilavsky E. Treatment of congenital cytomegalovirus beyond the neonatal period: an observational study. Eur J Pediatr 2020;179:807–12.

50. Turriziani Colonna A, Buonsenso D, Pata D, Salerno G, Chieffo DP, Romeo DM, et al. Long-term clinical, audiological, visual, neurocognitive and behavioral outcome in children with symptomatic and asymptomatic congenital cytomegalovirus infection treated with valganciclovir. Front Med 2020;7:268.

51. Suganuma E, Sakata H, Adachi N, Asanuma S, Furuichi M, Uejima Y, et al. Efficacy, safety, and pharmacokinetics of oral valganciclovir in patients with congenital cytomegalovirus infection. J Infect Chemother 2021;27:185–91.

52. Lanzieri TM, Caviness AC, Blum P, Demmler-Harrison G. Progressive, long-term hearing loss in congenital CMV disease after ganciclovir therapy. J Pediatr Infect Dis Soc 2022;11:16–23.

53. Kimberlin DW, Lin CY, Sánchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 2003;143:16–25.

54. Oliver SE, Cloud GA, Sánchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol 2009;46 Suppl 4(Suppl 4): S22–6.

55. Kimberlin DW, Jester PM, Sánchez PJ, Ahmed A, Arav-Boger R, Michaels MG, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. New Engl J Med 2015;372:933–43.

56. Korndewal MJ, de Vries J, de Melker HE. Valganciclovir for congenital cytomegalovirus. New Engl J Med 2015;372:2462–3.

57. Park A. Randomized controlled trial of valganciclovir for cytomegalovirus infected hearing impaired infants (ValEAR) [Internet]. Bethesda (MD): ClinicalTrials.gov; 2022 [cited 2022 Dec 10]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT03107871.

58. National Institute of Allergy and Infectious Diseases. Valganciclovir therapy in infants and children with congenital CMV infection and hearing loss [Internet]. ClinicalTrials.gov; 2021 [cited 2022 Dec 10]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT01649869.

59. Vossen ACTM. Congenital cytomegalovirus: efficacy of antiviral treatment (CONCERT 2) [Internet]. Bethesda (MD): ClinicalTrials.gov; 2021 [cited 2022 Dec 10]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT02005822.

60. Duval M, Park AH. Congenital cytomegalovirus: what the otolaryngologist should know. Curr Opin Otolaryngol Head Neck Surg 2014;22:495–500.

61. National Institute of Allergy and Infectious Diseases. Asymptomatic congenital CMV treatment [Internet]. Bethesda (MD): ClinicalTrials.gov; 2022 [cited 2022 Dec 10]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT03301415.

62. Demmler-Harrison GJ, Weisman LE. Congenital cytomegalovirus infection: management and outcome. Waltham (MA): UpToDate; c2019 [cited 2021 Dec 23]. Available from: https://www.uptodate.com/contents/congenital-cytomegalovirus-infection-management-and-outcome.

63. Kimberlin D. Congenital CMV and hearing loss in children up to 4 years of age: treating with valganciclovir therapy [Internet]. Bethesda (MD): ClinicalTrials.gov; 2022 [cited 2022 Dec 10]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT01649869.

64. Mareri A, Lasorella S, Iapadre G, Maresca M, Tambucci R, Nigro G. Anti-viral therapy for congenital cytomegalovirus infection: pharmacokinetics, efficacy and side effects. J Matern Fetal Neonatal Med 2016;29:1657–64.

65. Vora SB, Brothers AW, Waghmare A, Englund JA. Antiviral combination therapy for cytomegalovirus infection in high-risk infants. Antivir Ther 2018;23:505–11.

66. Rabinowicz S, Somech R, Yeshayahu Y. Foscarnet-related hypercalcemia during CMV treatment in an infant with SCID: a case report and review of literature. J Pediatr Hematol Oncol 2017;39:e173–5.

67. Acosta E, Brundage R, King J, Sanchez P, Sood S, Agrawal V, et al. Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation. Clin Pharmacol Ther 2007;81:867–72.

68. Schleiss MR. Congenital cytomegalovirus infection: update on management strategies. Curr Treat Options Neurol 2008;10:186–92.

69. Wang Y, Smith KP. Safety of alternative antiviral agents for neonatal herpes simplex virus encephalitis and disseminated infection. J Pediatr Pharmacol Ther 2014;19:72–82.

70. Ziv L, Yacobovich J, Pardo J, Yarden-Bilavsky H, Amir J, Osovsky M, et al. Hematologic adverse events associated with prolonged valganciclovir treatment in congenital cytomegalovirus infection. Pediatr Infect Dis J 2019;38:127–30.

71. Gwee A, Curtis N, Connell TG, Garland S, Daley AJ. Ganciclovir for the treatment of congenital cytomegalovirus: what are the side effects? Pediatr Infect Dis J 2014;33:115.

72. Faqi A, Klug A, Merker H, Chahoud I. Ganciclovir induces reproductive hazards in male rats after short-term exposure. Hum Exp Toxicol 1997;16:505–11.

73. Wutzler P, Thust R. Genetic risks of antiviral nucleoside analogues–a survey. Antiviral Res 2001;49:55–74.

74. Smiljkovic M, Le Meur JB, Malette B, Boucoiran I, Minsart AF, Lamarre V, et al. Blood viral load in the diagnostic workup of congenital cytomegalovirus infection. J Clin Virol 2020;122:104231.

75. Fischer C, Meylan P, Graz MB, Gudinchet F, Vaudaux B, Berger C, et al. Severe postnatally acquired cytomegalovirus infection presenting with colitis, pneumonitis and sepsis-like syndrome in an extremely low birthweight infant. Neonatology 2010;97:339–45.

76. Mehler K, Oberthuer A, Lang-Roth R, Kribs A. High rate of symptomatic cytomegalovirus infection in extremely low gestational age preterm infants of 22-24 weeks' gestation after transmission via breast milk. Neonatology 2014;105:27–32.

77. Okulu E, Akin İM, Atasay B, Ciftçi E, Arsan S, Türmen T. Severe postnatal cytomegalovirus infection with multisystem involvement in an extremely low birth weight infant. J Perinatol 2012;32:72–4.

78. Sunada M, Kinoshita D, Furukawa N, Kihara M, Nishimura A, Moriuchi M, et al. Therapeutic drug monitoring of ganciclovir for postnatal cytomegalovirus infection in an extremely low birth weight infant: a case report. BMC Pediatr 2016;16:1–4.

79. Goelz R, Hamprecht K, Klingel K, Poets CF. Intestinal manifestations of postnatal and congenital cytomegalovirus infection in term and preterm infants. J Clin Virol 2016;83:29–36.