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Congenital cytomegalovirus infection: Management and outcome

Congenital cytomegalovirus infection: Management and outcome
Author:
Gail J Demmler-Harrison, MD
Section Editors:
Morven S Edwards, MD
Leonard E Weisman, MD
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Jun 2022. | This topic last updated: Apr 01, 2021.

INTRODUCTION — Congenital cytomegalovirus (CMV) infection is the leading cause of nonhereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities, including cerebral palsy, intellectual disability, vision impairment, and seizures. Infants congenitally infected with CMV may benefit from antiviral therapy, especially if treatment is initiated within the first month of life.

The management and outcome of congenital CMV infection are reviewed below. The clinical features and diagnosis of congenital CMV infection, other TORCH infections, CMV in pregnancy, and CMV infections in older infants and children are discussed separately:

(See "Congenital cytomegalovirus infection: Clinical features and diagnosis".)

(See "Overview of TORCH infections".)

(See "Cytomegalovirus infection in pregnancy".)

(See "Overview of cytomegalovirus infections in children".)

TERMINOLOGY — Infants with congenital CMV infection are classified according to the presence or absence of apparent symptoms at the time of birth.

The term "symptomatic" refers to infants with one or more symptoms at birth. Infants with symptomatic congenital CMV infection may have mild, moderate, or severe manifestations. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Symptomatic neonate'.)

We use the term "primary neurophenotype" to refer to patients with only central nervous system manifestations. This is a newly described category of symptomatic infants, and the use of this term in the published literature is inconsistent. Infants in this category may appear completely healthy at birth or may have mild microcephaly. They usually are not diagnosed with congenital CMV infection a birth unless they are cared for at a center where all newborns are screened for CMV. As they grow, they develop more significant microcephaly and neurologic manifestations (eg, global developmental delay, abnormal tone, seizures). If neuroimaging is performed, it typically shows polymicrogyria or other cortical dysplasia. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Neuroimaging' and "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Primary neurophenotype'.)

The term "asymptomatic" refers to infants with no apparent symptoms at birth, although some of these infants may develop hearing loss or subtle symptoms later in life.

The term "asymptomatic with isolated hearing loss" refers to infants with isolated hearing loss at birth but no other symptoms. In studies of congenital CMV infection after the advent of universal newborn hearing screening, categorization of these infants as "symptomatic" or "asymptomatic" is inconsistent. Historically, they were often classified as "asymptomatic" because the hearing loss may not have been detected at birth. However, with universal newborn hearing screening, many such infants come to medical attention in the newborn period. We consider these infants to represent a distinct category because they are not truly asymptomatic, but their disease is generally milder than that of symptomatic infants.

SUPPORTIVE MEASURES — A small subset of neonates with symptomatic congenital CMV infection have severe, life-threatening presentation (eg, sepsis-like illness, myocarditis, viral-induced hemophagocytic lymphohistiocytosis, or severe neurologic involvement). (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Life-threatening disease'.)

Supportive measures for the symptomatic neonate with severe or life-threatening disease may include:

Fluid maintenance (see "Fluid and electrolyte therapy in newborns" and "Maintenance intravenous fluid therapy in children")

Transfusion of platelets and other blood products (see "Red blood cell transfusions in the newborn" and "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Platelet transfusion')

Control of seizures (see "Treatment of neonatal seizures")

Provision of oxygen and mechanical ventilator support (see "Overview of mechanical ventilation in neonates")

Nutritional support (see "Parenteral nutrition in infants and children")

Antimicrobial treatment for secondary bacterial infections (see "Management and outcome of sepsis in term and late preterm infants" and "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation")

ANTIVIRAL TREATMENT — Intravenous (IV) ganciclovir and its orally available prodrug, valganciclovir, are the first-line antiviral agents of choice for treatment of congenital CMV disease. These medications have been evaluated in multicenter, randomized clinical trials in newborns with symptomatic congenital CMV infection and have demonstrated a benefit when treatment is initiated within the first month of life [1-3]. The antivirals foscarnet and cidofovir are reserved for cases of refractory CMV disease, ganciclovir resistance, ganciclovir toxicity, and coinfection with adenovirus. (See 'Alternative antiviral agents' below.)

Whom to treat — The decision to treat an infected infant with antiviral therapy is based on the presence or absence of symptoms and on the immune status of the infant:

Symptomatic infection – We recommend antiviral treatment for infants with symptomatic congenital CMV infection (ie, infants with virologically confirmed congenital CMV and at least one end-organ symptom, including isolated central nervous system involvement [ie, the neurophenotype]) [4,5]. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Symptomatic neonate'.)

In infants with symptomatic congenital CMV infection, treatment with ganciclovir and valganciclovir has been shown to improve long-term audiologic and neurodevelopmental outcomes [1-3,6,7]. A randomized clinical trial comparing six weeks of ganciclovir therapy with no treatment in 100 newborns with symptomatic congenital CMV infection with central nervous system involvement showed protection against development or progression of hearing loss [1]. A total of 43 patients in the study had audiologic assessment both at baseline and at one year or beyond; 5 of 24 treated infants had worsening of hearing compared with 13 of 19 control patients. In addition, antiviral treatment was associated with improved head circumference growth and neurodevelopmental milestones during the first 6 to 12 months of life [1,2]. A subsequent randomized clinical trial evaluated six months versus six weeks of valganciclovir therapy in 96 infants with symptomatic congenital CMV infection with and without central nervous system involvement. Children who received six months of antiviral therapy were more likely to have improved hearing or maintain normal hearing (odds ratio 2.61, 95% CI 1.05-6.43) and higher language and receptive communication scores at 24 months [3].

Primary immunodeficiency – Antiviral therapy is also provided to infants with primary immunodeficiency, regardless of the degree of symptoms. (See "Severe combined immunodeficiency (SCID): An overview".)

Asymptomatic infection with isolated hearing loss – For infants with isolated hearing loss, expert opinion varies as to whether the benefits of antiviral therapy outweigh the risks [5,8]. There are no published clinical trials of antiviral therapy in this specific population; however, a multicenter clinical trial is ongoing [9]. At the author's institution, decisions regarding treatment of such infants are individualized based on the values and preferences of the parents or caregivers. We may observe the infant, offer antiviral treatment with valganciclovir, or enroll in a clinical trial.

We do not generally initiate antiviral therapy in the following circumstances, because there is insufficient evidence of benefit to outweigh the potential risks:

In utero – Maternal antiviral therapy for prevention or treatment of fetal CMV is not routinely recommended. This issue is discussed in greater detail separately. (See "Cytomegalovirus infection in pregnancy", section on 'Prenatal drug therapy'.)

Asymptomatic newborns with normal hearing – Antiviral therapy for asymptomatic infants with congenital CMV infection has not been conclusively shown to improve audiologic outcomes [10,11]. In a small clinical trial involving 23 newborns with asymptomatic congenital CMV infection who were randomly assigned to three weeks of ganciclovir therapy or no treatment, delayed-onset hearing loss occurred in none of the nine children in the ganciclovir group who were available for follow-up compared with two of nine in the untreated group; five children were lost to follow-up over the 10-year study period [11]. While the results from this study are promising, the small number of children treated precludes drawing firm conclusions as to whether therapy is truly beneficial. Further studies with larger numbers of asymptomatic infants are needed to identify both benefits and risks of antiviral therapy in this group. At the author's institution, newborns identified to have congenital CMV infection who are asymptomatic with normal hearing are typically observed and followed carefully for signs of clinical disease or hearing loss. A phase II, open-label clinical trial evaluating valganciclovir treatment in these newborns is underway and may provide answers to this important clinical question [12]. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Asymptomatic infection'.)

Timing — Antiviral therapy should be initiated as soon as virologic testing is confirmed. Clinical trials investigating the effectiveness of antiviral therapy in congenital CMV disease have found a benefit when treatment is initiated within the first 30 days of life. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Interpretation/diagnosis' and 'Whom to treat' above.)

Further studies are required to determine if starting antiviral therapy after one month of age is beneficial. A clinical trial evaluating valganciclovir treatment in infants and toddlers (ages one month to three years) with congenital CMV-related hearing loss has recently been completed, but the results are not yet available [13].

Pretreatment evaluation — Before starting antiviral treatment, the infected neonate should undergo a comprehensive evaluation [4,5]. At the author's institution, this includes the following:

Thorough physical examination to identify the full extent of CMV disease involvement.

Complete blood count, including differential and platelet count to establish baseline levels.

Liver transaminases, and total and direct bilirubin to establish baseline levels.

Blood urea nitrogen (BUN) and creatinine to determine if dose adjustment of antiviral medications is warranted.

Neuroimaging with ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) to assess the degree of central nervous system involvement. Ultrasound is the preferred initial study for most infants, as discussed separately. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Post-diagnosis evaluation'.)

Audiologic testing.

Ophthalmologic examination.

CMV DNAemia by quantitative polymerase chain reaction (PCR) to establish baseline level of viremia.

Antiviral regimen — The choice of initial antiviral agent (IV ganciclovir versus oral valganciclovir) depends upon the severity of disease (table 1 and algorithm 1):

Life-threatening disease — We generally use IV ganciclovir initially for treatment of congenital CMV infection in infants with any of the following (algorithm 2):

Viral sepsis-like syndrome

Viral-induced hemophagocytic lymphohistiocytosis

Pneumonitis

Myocarditis

Severe hepatitis

Enterocolitis

Severe and refractory thrombocytopenia

Sight-threatening retinitis

Severe neurologic disease

Underlying primary immune disorder (eg, severe combined immunodeficiency [SCID]) regardless of degree of symptoms

We also use IV ganciclovir in patients gastrointestinal problems, which may interfere with absorption of enteral medications.

For infants with severe sight-threatening CMV-associated retinitis, systemic antiviral therapy may not be sufficient and intraocular antiviral therapy may be required. (See 'Chorioretinitis' below.)

Infants with primary immune disorders are at high risk of having severe manifestations and for developing resistant CMV strains. If the infant is being considered for bone marrow transplant in the immediate future, we may initially start two antivirals (ganciclovir and foscarnet) to avoid the emergence of resistance. (See 'Antiviral resistance' below.)

Infants with the above conditions who lack life-threatening manifestations may be started on oral valganciclovir if they are well appearing or only mildly symptomatic, have a stable respiratory status (in room air or low supplemental oxygen), are tolerating oral feeds, and are gaining weight. (See 'Non-life-threatening disease' below.)

The dose of ganciclovir is 6 mg/kg per dose administered IV every 12 hours [1,2,4,14,15]. The dose must be adjusted in neonates with renal failure. The dose should be increased with infant weight gain to maintain a dose of 6 mg/kg per dose. Adequate antiviral dosing is important to avoid resistance. Subtherapeutic dosing encourages the emergence of resistant strains. (See 'Antiviral resistance' below.)

Ganciclovir should be administered through a central venous catheter when possible. If brief ganciclovir treatment (<2 weeks) is anticipated, a well-functioning peripheral IV may be used for administration, provided that the IV site is carefully monitored during ganciclovir infusion. (See 'Adverse effects' below.)

Infants may be transitioned to oral valganciclovir if clinically stable and able to take oral medications, usually after two to six weeks. We do not routinely recommend more than six weeks of IV ganciclovir, due to risks of toxicity with prolonged treatment. After transition to oral valganciclovir, therapy should continue for a total of six months in most cases [5].

More than six months of valganciclovir therapy may be given to infants with persistent viremia, persistent retinitis, and persistent liver disease and for infants with primary immune disorder. We suggest monitoring CMV DNAemia in severely symptomatic infants and prolonging antiviral treatment if viremia has not resolved after six months. (See 'Treatment response' below.)

A case series of 23 infants treated with 12 months of valganciclovir found prolonged treatment was safe and was associated with improved audiologic outcomes compared with historical controls who received six weeks of therapy [15].

If CMV viremia persists, and particularly if CMV viral load levels steadily or significantly increase on adequate antiviral therapy, emergence of antiviral resistance should be suspected. (See 'Antiviral resistance' below.)

Non-life-threatening disease — Non-life-threatening disease is defined more by the infant's general medical condition than by CMV-specific symptoms (table 1). Infants with non-life-threatening disease are those that meet all of the following criteria:

Well appearing or only mildly symptomatic, being managed in the newborn nursery or at home

Stable respiratory status (in room air or low supplemental oxygen)

Tolerating oral feeds

Stable and gaining weight

These infants generally lack severe end-organ involvement. Examples of non-life-threatening disease include microcephaly or intracranial calcifications without seizures or encephalopathy, jaundice or hepatosplenomegaly without severe hepatitis or refractory thrombocytopenia, and isolated hearing loss.

Infants with non-life-threatening disease are treated with valganciclovir oral solution and monitored closely for clinical response (table 1 and algorithm 3). (See 'Treatment response' below.)

The recommended dose of valganciclovir is 16 mg/kg per dose administered orally every 12 hours [4]. The dose must be adjusted in neonates with renal failure. The dose should be increased with infant weight gain to maintain a dose of 16 mg/kg per dose.

In clinical studies, oral valganciclovir achieved plasma levels and clinical effectiveness similar to those of IV ganciclovir [16-20]. Only valganciclovir clear oral solution from the manufacturer has been studied in patients with congenital CMV infections [16]. Pharmacy compounded suspensions should not be used.

We suggest six months of oral valganciclovir therapy in most cases of non-life-threatening infection.

Monitoring

Adverse effects — We initially obtain the following blood tests weekly in infants receiving ganciclovir or valganciclovir therapy to monitor for signs of toxicity [4]:

Complete blood count with differential and platelet count – The complete blood count is monitored weekly for the first six weeks and if stable; it is subsequently monitored every two to four weeks throughout the treatment course.

Liver function tests (aspartate aminotransferase, alanine aminotransferase, total and direct bilirubin), monitored weekly initially and then monthly once stable.

Kidney function tests (BUN and creatinine), monitored weekly initially and then every three months once stable.

Adverse effects associated with ganciclovir and valganciclovir treatment include:

Neutropenia – Neutropenia occurs in 25 to 60 percent of neonates treated with IV ganciclovir and approximately 20 percent of infants treated with oral valganciclovir [1-3,21]. It is rarely severe and usually resolves with holding the antiviral for one to seven days and reinstituting the same dose after the absolute neutrophil count (ANC) has recovered. Treatment discontinuation may be necessary if neutropenia recurs. Reinstituting one-half the antiviral dose may be helpful in select cases; however, we suggest not routinely using a lower dose of ganciclovir, because this encourages the emergence of ganciclovir resistance.

Our approach to the management of ganciclovir-induced neutropenia is as follows:

If the ANC falls below 500/microL we recheck the blood count the following day. If the ANC is below 500/microL on two consecutive days, we discontinue antiviral therapy and investigate for other causes of neutropenia (eg, concurrent viral infection or other medications). (See "Overview of neutropenia in children and adolescents", section on 'Classification and etiology of isolated neutropenia'.)

Following discontinuation of therapy, the ANC is monitored two to three times per week and, once it has recovered to >1000/microL, antiviral therapy is reinstituted at the previous dose.

If the ANC does not recover promptly following discontinuation of therapy, administration of an alternative antiviral agent such as foscarnet or cidofovir may be warranted, particularly if the infant has severe, life-threatening symptoms of CMV infection. (See 'Alternative antiviral agents' below.)

Alternative approaches to management of ganciclovir-induced neutropenia include dose adjustment and treatment with granulocyte colony-stimulating factor (G-CSF). We reserve the use of G-CSF for infants with severe CMV disease who are intolerant to the usual dosing regimens. We do not use it routinely. (See "Drug-induced neutropenia and agranulocytosis", section on 'Granulocyte colony-stimulating factor'.)

In a clinical trial, neutropenia occurred in 29 of 46 infants treated with ganciclovir. Dose adjustment was required in 14 patients, two patients required treatment with granulocyte colony-stimulating factor and four patients required discontinuation of ganciclovir. The mean time (±standard deviation) of onset of neutropenia was 14.2 (±12.3) days [1].

Some infants with congenital CMV infection have a baseline neutropenia, with a relative lymphocytosis. In these cases, antiviral therapy may still be instituted and ANC observed closely.

Thrombocytopenia – Thrombocytopenia (platelets <50,000 cells/microL) has been reported to occur in 6 percent of infants during ganciclovir therapy [21,22]. However, infants with congenital CMV infection often have low platelet counts at birth and the relative contribution of ganciclovir to the thrombocytopenia is unclear. In a randomized controlled trial, thrombocytopenia occurred at a similar rate in ganciclovir-treated and untreated infants (7 versus 5 percent, respectively) [1]. Worsening thrombocytopenia during antiviral therapy while CMV DNAemia levels are declining may suggest drug-induced thrombocytopenia or a splenic sequestration effect if the infant has significant splenomegaly. (See "Neonatal thrombocytopenia: Etiology", section on 'Drug-related thrombocytopenia' and "Neonatal thrombocytopenia: Etiology", section on 'Sequestration and trapping'.)

Hepatotoxicity – Hepatotoxicity has been observed in infants receiving ganciclovir, particularly at doses higher than 6 mg/kg [21,22]. Mild elevations in transaminases (<100 int. units/L) are common, especially in infants receiving valganciclovir, because liver metabolism is required to cleave off the valine ester of the compound. Such mild elevations are generally not of concern.

Ganciclovir or valganciclovir should be discontinued if transaminases rise to >250 int. units/L with no alternative cause (eg, concurrent viral infection or other medications). (See "Hepatitis viruses and the newborn: Clinical manifestations and treatment".)

Transaminase levels should then be monitored weekly and when they decline, antiviral therapy can be restarted. If transaminase levels rise again, ganciclovir should be stopped and infants with mild CMV disease can be monitored closely off antiviral therapy. Infants with severe or life-threatening infection may require treatment with an alternative antiviral agent. (See 'Alternative antiviral agents' below.)

Nephrotoxicity – Elevated serum creatinine has been reported in <1 percent of neonates treated with ganciclovir and valganciclovir [21,22]. The dose of ganciclovir and valganciclovir should be adjusted in renal failure.

IV catheter events – Events related to the IV catheter during ganciclovir treatment are common. Extravasation of the IV ganciclovir solution may produce local reaction, ulcers, and scarring. Therefore, we recommend ganciclovir be administered through a central venous catheter when possible. If brief ganciclovir treatment (<2 weeks) is anticipated, a well-functioning peripheral IV may be used for administration, provided the IV site is carefully monitored during ganciclovir infusion. If signs of extravasation are observed, the infusion should be discontinued and other IV access sought. If ganciclovir therapy is anticipated for ≥2 weeks, we recommend placement of a peripherally inserted central catheter or other central venous access.

Catheter-associated infection is a potential risk in infants receiving long-term IV ganciclovir therapy, particularly in infants with primary immunodeficiency or ganciclovir-induced neutropenia. In a clinical trial, 7 percent (3 of 46) of treated infants developed catheter infections, and in some case reports up to 67 percent developed catheter infections [1,7].

Long-term effects – There is no evidence that ganciclovir or valganciclovir treatment in the newborn period leads to any significant long-term adverse effects despite evidence that these drugs may cause infertility in animal models [22,23].

Treatment response — Treatment response can be assessed by monitoring clinical symptoms and level of viremia.

Clinical symptoms are monitored with:

Regular general physical examination, including growth parameters and head circumference

Neurologic examination

Hearing evaluation every three to six months

Eye examination every three to six months; more frequent evaluations are required in infants with chorioretinitis (see 'Chorioretinitis' below)

Level of viremia is measured with quantitative CMV DNA PCR (CMV DNAemia) in whole blood or plasma.

Our practice is to measure CMV DNAemia in all infants undergoing antiviral therapy for congenital CMV. The frequency of measurement depends on the severity of illness:

Life-threatening disease – We monitor CMV DNAemia levels weekly initially in infants with evidence of life-threatening end-organ disease and in infants with primary immunodeficiency (see 'Life-threatening disease' above). Once stable, CMV DNAemia levels should be monitored every two to four weeks.

Non-life-threatening disease – We monitor CMV DNAemia levels at the onset of treatment, at three months of age, and at six months of age in infants with non-life-threatening disease receiving oral valganciclovir in the outpatient setting. (See 'Non-life-threatening disease' above.)

CMV DNAemia levels measured by quantitative PCR usually decline by the second to fourth week of ganciclovir or valganciclovir therapy. In most cases, the goal of therapy is an undetectable or near undetectable CMV DNAemia level before stopping treatment. However, levels may not decline to undetectable in some patients. Clinical trial data have correlated low viral load with improved hearing outcomes if treatment is continued for six months [3].

Not all experts agree on routinely measuring quantitative CMV DNAemia levels, because their significance and value in determining duration of treatment has not been established.

Treatment failure — Evidence of treatment failure includes any of the following:

Progressive end-organ disease despite adequate treatment

Rising CMV DNAemia levels after two weeks of treatment (see 'Treatment response' above)

Sustained significant increase in CMV DNAemia levels after an initial decline (see 'Treatment response' above)

Treatment failure may occur because of the host response (ie, immune dysfunction), emergence of a ganciclovir-resistant CMV strain, or a combination of both.

Infants at highest risk for treatment failure are those with primary immune deficiency (especially dysfunction of T cells and natural killer cells) and those on immunosuppressive therapy such as glucocorticoids and chemotherapy. In some cases refractory CMV disease may be the first indication of immunocompromise and additional testing for underlying immunodeficiency may be warranted. (See "Severe combined immunodeficiency (SCID): An overview".)

Antiviral resistance — Antiviral resistance is uncommon but has been documented in congenitally infected infants treated with ganciclovir and valganciclovir [24-26]. Resistance should be suspected if levels of DNAemia rise significantly during therapy.

Resistant strains of CMV may compartmentalize and cause progressive disease within a single organ (eg, eye, brain, or lungs) [27]. Hence, antiviral resistance should also be suspected when there is progressive end-organ disease despite an appropriate decline in CMV DNAemia levels. Serial retinal examinations and/or measurement of viral titers in the affected organ (eg, cerebrospinal fluid or respiratory secretions) can be helpful in such cases.

Most ganciclovir-resistant CMV strains are susceptible to foscarnet but may exhibit cross resistance to cidofovir [27]. Strains simultaneously resistant to ganciclovir, cidofovir, and foscarnet rarely may occur. Adequate antiviral dosing is important to avoid resistance; subtherapeutic dosing encourages the emergence of resistant strains.

Management of suspected or documented antiviral resistance during treatment for congenital CMV disease depends on the severity of disease and the immune status of the infant. If the infant is otherwise stable and doing well, then cessation of antiviral therapy may be a safe option [24]. However, if the infant remains seriously ill or has a primary immune disorder, addition of another antiviral (eg, foscarnet) may be indicated. Laboratory testing should be used to confirm antiviral resistance when it is clinically suspected; however, clinical antiviral resistance may be present even if a mutation is not detected on formal testing. If the clinical suspicion for antiviral resistance is high and the infant remains seriously ill, the antiviral regimen should be modified while awaiting test results. (See 'Testing for antiviral resistance' below and 'Alternative antiviral agents' below.)

Testing for antiviral resistance — Testing for antiviral resistance is accomplished using either genotypic or phenotypic assays.

Genotypic assays detect viral gene sequence variations known to be associated with development of antiviral resistance. Genotypic assays are preferred because they are standardized, available in clinical reference laboratories, and yield results more rapidly than phenotypic assays.

Phenotypic assays directly measure drug susceptibilities of CMV viral isolates. Phenotypic assays are generally not used, because they are time-consuming and not standardized for clinical use.

Alternative antiviral agents — Foscarnet and cidofovir are not used routinely for treatment of congenital CMV infection, and data regarding their use in this setting are limited [28-30]. These agents may be used in select cases if there is suspected or confirmed ganciclovir-resistance or if significant toxicity is encountered during ganciclovir or valganciclovir therapy. (See 'Adverse effects' above.)

The decision to use one of these alternative agents for treatment of congenital CMV infection also depends on the severity of illness. If the infant is otherwise stable and doing well, then cessation of antiviral therapy may be a safer option rather than transitioning to foscarnet or cidofovir. Consultation with a pediatric infectious disease expert is advised.

We have used combination ganciclovir and foscarnet treatment in CMV infected infants with an underlying primary immune disorder of T cell or natural killer cell function, especially if they fail to respond promptly to monotherapy with ganciclovir.

Foscarnet is preferred over cidofovir in management of ganciclovir resistance because cross resistance occurs less frequently. However, cidofovir may be used if genotypic testing reveals both ganciclovir and foscarnet resistance or if metabolic disturbances associated with foscarnet preclude its use.

Appropriate dosing and monitoring for these antivirals is as follows:

Foscarnet – The recommended induction dose of foscarnet is 60 mg/kg per dose administered IV every eight hours for two to three weeks, followed by maintenance therapy at a dose of 90 mg/kg per dose once daily for two to three weeks.

Toxicity associated with foscarnet includes renal insufficiency and electrolyte derangements (particularly hypocalcemia or hypercalcemia, but also metabolic acidosis, hyper-/hypophosphatemia, hypokalemia, hypomagnesemia, and hyponatremia). Infants treated with foscarnet should have BUN, creatinine, and serum electrolytes (including sodium, potassium, calcium, magnesium, and phosphorus levels) monitored at least twice weekly. Providing adequate pre-dose hydration may minimize renal toxicity effects of foscarnet administration.

Cidofovir – The recommended dose of cidofovir is 5 mg/kg per dose administered IV every seven days for two weeks, then every other week for an additional four weeks. An alternative dosing regimen of 1 mg/kg per dose three times per week has also been used.

To reduce renal and metabolic adverse effects, cidofovir should be administered with probenecid one hour before and eight hours after the dose of cidofovir. In addition, an IV fluid bolus should be given one hour before and one hour after the cidofovir infusion. The amount of fluid given will depend on the ability of the infant to tolerate the fluid bolus.

Infants receiving cidofovir should have blood tests to monitor for toxicities before each dose. In addition to renal and metabolic adverse effects, toxicity associated with cidofovir includes neutropenia and hepatotoxicity. Monitoring includes serum BUN, creatinine, calcium, magnesium, phosphorous, and uric acid levels; urine protein measurement; liver function tests; and complete blood count with differential. In addition, infants should have an ophthalmologic evaluation every one to two weeks while receiving cidofovir.

Special circumstances

Chorioretinitis — In addition to treatment with IV ganciclovir (see 'Antiviral regimen' above), infants with chorioretinitis require consultation with a pediatric ophthalmologist or retinal specialist. Monitoring of the retinal lesions every 7 to 10 days is recommended. If progression occurs, additional treatments may be indicated. For infants with severe sight-threatening CMV-associated chorioretinitis, systemic antivirals may not penetrate the eye in sufficient levels to adequately treat active CMV, and intravitreal antiviral therapy may be required. Intravitreal ganciclovir and foscarnet have been used in such cases [25,31].

Coinfection with other viruses — On rare occasions, infants with congenital CMV have coinfections with other viruses. Infants with congenital CMV disease who are coinfected with acyclovir-resistant herpes simplex virus may be treated with foscarnet. In infants coinfected with adenovirus, cidofovir may be preferred over ganciclovir to provide cross coverage of both CMV and adenovirus. (See 'Alternative antiviral agents' above.)

OUTCOME — The outcome of congenital CMV infection depends upon the clinical pattern of disease at birth, as well as antiviral treatment provided in the newborn period.

In long-term follow-up studies, most of which were performed before treatment of symptomatic congenital CMV was routinely practiced, late sequelae included [32-35]:

Hearing loss (50 to 58 percent)

Intellectual disability (intelligence quotient <70; 47 to 55 percent)

Microcephaly (37 percent)

Strabismus (25 to 30 percent)

Dental disease (27 percent)

Seizures (23 percent)

Cortical visual impairment (14 to 22 percent)

Chorioretinitis (20 percent)

Cerebral palsy (13 to 27 percent)

Death after the newborn period (1.7 to 5.8 percent)

In a longitudinal study of 178 infants with symptomatic congenital CMV infection followed for an average of 4.6 years, 72 percent were found to have at least one disability and 42 percent had multiple long-term sequelae [33].

In symptomatic infants, treatment with antiviral medications in early infancy appears to reduce long-term sequelae, particularly hearing loss [1-3,6,7]. However, further longitudinal studies of treated infants are needed to fully understand the impact of antiviral treatment on long-term disability.

Infants with asymptomatic infection at birth are less likely to experience long-term disabilities [36,37]. In a longitudinal study of 135 asymptomatic infants followed for 5 to 10 years, 14 percent developed long-term sequelae (7 percent had mild impairment, 4 percent had moderate impairment, and 3 percent had severe impairment) [36].

Poor long-term neurodevelopmental outcome is more likely in infants with microcephaly, chorioretinitis, and abnormal neuroimaging findings (particularly intracranial calcifications) in the newborn period. The absence of these factors predicts a normal or near-normal cognitive outcome for most infants [38-40]. The presence of petechiae and intrauterine growth restriction in the newborn are predictive of hearing loss [41]; however, hearing impairment is more likely in infants with central nervous system involvement compared with those who have transient neonatal findings or only a petechial rash [42].

Detection and quantitation of viremia may be helpful in predicting long-term outcomes, particularly hearing loss. A number of studies have identified an association between CMV viral load and hearing loss [43-47]. Low or no detectable virus in the blood during the neonatal period is associated with a low risk for hearing deficit later in life. However, this test has a poor positive predictive value for predicting hearing loss among asymptomatic newborns [48].

LONG-TERM FOLLOW-UP — All children with congenital CMV infection (including those who are symptomatic at birth and those who are asymptomatic) should be followed throughout childhood and into adulthood for evidence of long-term effects of CMV.

Hearing loss – The hearing loss in congenital CMV is progressive over the course of the lifetime. Hearing evaluations are recommended every three to six months during the first three years of life and annually thereafter until at least 18 years of age [49-51]. If hearing loss is detected, assessments should continue into adulthood to monitor for hearing loss progression. Vestibular disorders are also common and can negatively impact postural and motor development [52,53].

Children identified with hearing deficits may benefit from referral to early intervention programs and educational accommodations such as preferential classroom seating. Hearing aids may be needed, and, if progression to profound hearing loss occurs, cochlear implantation may be indicated. (See "Hearing loss in children: Treatment".)

In children with congenital CMV-related hearing loss, middle ear effusions can compound the problem, with associated changes in behavior or school performance. Clinicians should have a low threshold for referral to an otolaryngologist for evaluation and possible tympanostomy tube placement [54]. (See "Otitis media with effusion (serous otitis media) in children: Management".)

Central nervous system manifestations – Central nervous system manifestations (intellectual disability, cerebral palsy, and seizures) may require special education services and speech, language, occupational, and/or physical therapy [50]. Severely affected children with spasticity may require involvement of orthopedics and physical medicine consultations to determine the need for medicines to relieve spasticity, mobility aids, orthotics, or orthopedic procedures. (See "Intellectual disability (ID) in children: Management, outcomes, and prevention" and "Cerebral palsy: Overview of management and prognosis".)

Neurologic consultation may be indicated for seizure management. Rarely, seizures associated with polymicrogyria and other malformations of cortical development are refractory to medical management and require neurosurgical interventions. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)

Behavioral and developmental disorders – Congenital CMV may also be associated with behavioral and developmental disorders, such as autism spectrum disorder, attention deficit, and hyperactivity, and these have been observed and diagnosed in children with congenital CMV, especially those with symptomatic infection [55,56]. However, when systematically studied or reviewed, the direct role of CMV in autism has not been convincingly established and requires further study [56]. All children with congenital CMV should undergo routine developmental screening to facilitate early recognition of these problems, as discussed separately. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Developmental-behavioral surveillance and screening in primary care" and "Autism spectrum disorder: Surveillance and screening in primary care" and "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis".)

Eye disease – Chorioretinitis, retinopathy, optic atrophy, and strabismus require specialized management. Cortical visual impairment may also occur, especially in severely affected newborns with central nervous system involvement. Most ocular manifestations associated with congenital CMV are detectable at birth; however, later-onset retinitis can occur and may be severe and sight-threatening. Therefore, repeat ophthalmologic evaluations are recommended for newborns with symptomatic congenital CMV during the first year of life and then annually thereafter. Special therapies for the visually impaired or specialized cortical visual impairment therapies also may be helpful. (See "Vision screening and assessment in infants and children" and "Evaluation and management of strabismus in children".)

Dental disease – Congenital CMV is associated with hypoplasia and hypocalcification of tooth enamel, affecting mainly primary dentition [32,57]. Affected teeth are susceptible to mechanical injury from minor trauma, and caries occurs frequently. Regular dental visits are an important component of the long-term care of these children. (See "Preventive dental care and counseling for infants and young children".)

Liver disease – Chronic hepatitis as a result of congenital CMV disease is uncommon, and discerning which role, if any, CMV may be playing in chronic liver disease in a congenitally infected infant can be challenging. Abnormal liver function tests usually resolve during the first few weeks of life. Hepatomegaly usually resolves by three to six months. Infants with congenital CMV and persistent liver dysfunction or persistent direct hyperbilirubinemia should be evaluated for biliary atresia, alpha-1 antitrypsin deficiency, or other genetic or metabolic disorders since CMV and another diagnosis affecting liver function may coexist in the same infant and present a diagnostic challenge. (See "Biliary atresia" and "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'.)

PREVENTION — Prevention strategies are discussed separately and include:

Personal protective measures (see "Cytomegalovirus infection in pregnancy", section on 'Pregnant women')

Passive immunoprophylaxis in pregnant women with primary CMV infection (see "Cytomegalovirus infection in pregnancy", section on 'CMV immune globulin')

Vaccination (see "Cytomegalovirus infection in pregnancy", section on 'Vaccine development')

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: TORCH infections".)

SUMMARY AND RECOMMENDATIONS

Congenital cytomegalovirus (CMV) infection is the leading cause of nonhereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities. Infants congenitally infected with CMV may benefit from antiviral therapy, especially if treatment is initiated within the first month of life. (See 'Introduction' above.)

Infants with congenital CMV infection are classified according to the presence or absence of apparent symptoms at birth:

"Symptomatic" refers to infants with one or more symptoms at birth. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Symptomatic neonate'.)

The "primary neurophenotype" is a subcategory of symptomatic infection referring to patients with only central nervous system manifestations. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Primary neurophenotype'.)

"Asymptomatic" refers to infants with no apparent symptoms at birth.

"Asymptomatic with failed hearing screen" refers to infants with isolated hearing loss at birth but no other symptoms. These infants are not truly asymptomatic, but their disease is generally milder than that of symptomatic infants. (See 'Terminology' above.)

We recommend antiviral treatment for symptomatic infants with virologically proven CMV infection and at least one end-organ symptom (Grade 1B). In infants with symptomatic congenital CMV infection, treatment with ganciclovir and valganciclovir has been shown to improve long-term audiologic and neurodevelopmental outcomes. (See 'Whom to treat' above.)

The choice of initial antiviral agent depends on the severity of the infection, clinical stability of the infant, and ability to tolerate oral medications (see 'Antiviral regimen' above):

For infants with life-threatening disease, we suggest ganciclovir as the initial antiviral agent (table 1 and algorithm 2) (Grade 2C). The dose of ganciclovir is 6 mg/kg per dose administered intravenously (IV) every 12 hours. (See 'Life-threatening disease' above.)

For infants with non-life-threatening disease, we suggest valganciclovir as the antiviral agent (table 1 and algorithm 3) (Grade 2C). The dose of valganciclovir is 16 mg/kg per dose administered orally every 12 hours. (See 'Non-life-threatening disease' above.)

Foscarnet or cidofovir are not routinely used for treatment of congenital CMV disease but may be indicated in special circumstances in high-risk infants. (See 'Alternative antiviral agents' above.)

We provide a minimum of six months of antiviral therapy to all infants with symptomatic congenital CMV infection. Infants with life-threatening symptoms receive two to six weeks of IV ganciclovir treatment initially and then transition to oral valganciclovir, whereas infants with non-life-threatening symptoms receive oral valganciclovir for the entire six-month treatment course. We prolong treatment in severely affected infants if persistent viremia is detected or in infants with primary immune disorders. (See 'Antiviral regimen' above.)

Monitoring for toxicity during antiviral treatment includes:

Complete blood count with differential and platelet count to detect drug-induced neutropenia and thrombocytopenia

Liver function tests (aspartate aminotransferase, alanine aminotransferase, total and direct bilirubin) to detect drug-induced hepatitis

Kidney function tests (blood urea nitrogen [BUN] and creatinine) to detect drug-induced nephrotoxicity and to determine if dose adjustment is necessary

Blood tests should be monitored weekly during the first few weeks of therapy and can then be spaced out if stable. (See 'Monitoring' above and 'Adverse effects' above.)

Treatment response is assessed with clinical evaluation and measurement of viremia levels. We monitor CMV DNAemia levels by quantitative polymerase chain reaction (PCR) throughout antiviral therapy. DNAemia levels usually decline by the second to fourth week of antiviral therapy. In most cases, the goal of therapy is a nondetectable CMV DNAemia level before stopping treatment, assuming a minimum treatment period of six months. Antiviral resistance should be suspected in infants with progressive end-organ disease despite adequate treatment, rising DNAemia levels after two weeks of treatment, or a sustained increase in DNAemia levels after an initial decline. (See 'Monitoring' above and 'Treatment failure' above and 'Antiviral resistance' above.)

Long-term sequelae following congenital CMV infection include hearing loss, intellectual disability, seizures, dental disease, vision impairment, and cerebral palsy. Sequelae are common in infants with symptomatic infection at birth. Infants who are asymptomatic at birth are at risk for late-onset hearing loss, but other complications are uncommon. (See 'Outcome' above.)

Children with congenital CMV should be followed throughout childhood and adolescence and into adulthood for evidence of long-term effects of CMV. (See 'Long-term follow-up' above.)

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References