Mark R Schleiss, MD

The advent of the congenital Zika virus epidemic in 2016 focused considerable and well-deserved attention on the recognition and prevention of this infection. Even as this tragedy continues to unfold, however, the ongoing problem of congenital cytomegalovirus (cCMV) infection deserves similar scrutiny. This article provides an overview of the impact of cCMV on pediatric practice, with an emphasis on evolving concepts in maternal and newborn screening, counseling and education, diagnosis in the newborn, and medical management of children with CMV infection.

Congenital infections with CMV are common and appear to be underrecognized. In the United States, the Centers for Disease Control and Prevention has estimated an overall birth prevalence of 0.65%.

 Congenital infections are even more prevalent in the developing world, with estimates of rates as high as 6.5% in some populations.

 In the United States, this corresponds to over 25,000 newborns every year with cCMV. Considerable variation also has been seen in birth prevalence based on maternal age, race, socioeconomic status, and the entire spectrum of the social determinants of health.

 Rates of cCMV are highest in black infants, making cCMV an example of a disease reflecting health disparities nationally.

To put this all in perspective, as of June 2016, there had been 7830 suspected cases of congenital Zika syndrome reported to the Brazilian Ministry of Health.

 The largest total of US cases of congenital infection with another teratogenic virus, rubella, was in 1969, when 57,686 cases were reported.

 Thus, the total number of cases of cCMV in this country (and globally) far exceeds the cases of congenital Zika syndrome and is similar in scope to the magnitude of congenital rubella syndrome observed in the prevaccine era.

Given the high prevalence of cCMV, why isn’t it more commonly recognized by clinicians? One important issue is the lack of knowledge and awareness not only among the lay public but also among healthcare providers, including obstetricians and pediatricians. Women of childbearing age in particular lack knowledge about the risks associated with cCMV. Transmission of CMV requires exposure to infectious body fluids including urine, saliva, blood, and breast milk. Women who have children in group daycare are at particular risk because CMV shedding rates are high in infants and toddlers attending daycare centers. Toddlers bring CMV home from the daycare center and expose their susceptible parents to the virus, resulting in infections that often are asymptomatic or minimally symptomatic but can lead to congenital transmission if that child’s mother is pregnant. Surveys have shown that women are less well informed about cCMV than they are about neural tube defects, fetal alcohol syndrome, Down syndrome, and toxoplasmosis, even though all these threats to healthy pregnancy are less common than CMV.

 Thus, there is a great unmet need for programs that can increase the public’s familiarity with cCMV.

Another major challenge that diminishes overall awareness of cCMV is the recognition that the majority of infants with cCMV (85%-90%) are asymptomatic at birth.

 In the 10% to 15% of infants who do have signs or symptoms at birth, clinical manifestations may include growth retardation, petechiae, hepatosplenomegaly, microcephaly, jaundice, seizures, and rashes (Table 1). Symptomatic infants are more likely to have long-term neurodevelopmental sequelae, including mental retardation, seizure disorders, cerebral palsy, sensorineural hearing loss (SNHL), microcephaly, and learning disabilities.

 Of these sequelae, SNHL is the most common.

It is important to keep in perspective that asymptomatic cCMV is not innocuous. Asymptomatic infection can portend long-term risk, particularly as it relates to SNHL. Approximately 22% to 65% of children with symptomatic disease at birth and 6% to 23% of children with asymptomatic cCMV infection will have SNHL following congenital CMV infection.

 Also of note is that SNHL caused by cCMV infection may not be present at birth and will not be noticeable until later in childhood. An infant with cCMV may hear normally at birth, only to have progression to severe SNHL in early childhood.

The fluctuating and (in many cases) delayed nature of cCMV-associated SNHL means that the majority of cases will be missed by routine newborn hearing screening.

 This provides a compelling rationale for universal CMV screening for all newborn infants. Such universal screening could create an opportunity to provide any infant (even asymptomatic babies) with known cCMV with serial, regular audiologic assessment to facilitate early intervention for those infants demonstrating evidence of SNHL.

The cornerstone of diagnosis of cCMV is based on virology, not serology. Although the term “TORCH titers” is unfortunately still used in clinical practice, this nomenclature should be abandoned because antibody studies are rarely useful in the workup and management of congenital viral infections. The traditional gold standard for diagnosis of cCMV has been demonstration of virus by culture in specimens of saliva, urine, or blood obtained from the infected newborn. Few diagnostic laboratories offer culture today, however, and virologic diagnosis is now more commonly predicated on identification of viral DNA by polymerase chain reaction (PCR) assay. A PCR of urine or saliva is equally definitive in making the diagnosis of cCMV.

Most experts recommend obtaining blood PCR for CMV DNA in addition to urine and saliva samples. The finding of CMV immunoglobulin (Ig) G antibodies is not informative because it neither confirms that an infant has congenital CMV (as transplacental transfer of IgG can occur without bona fide infection) nor excludes the possibility of congenital CMV infection (as late gestation transmission can occur from mother to fetus prior to appearance of IgG antibodies). Evaluation of neonatal serum for IgM antibodies can be useful, but the test is relatively insensitive and should not be relied on to confirm or exclude the diagnosis.

One critically important element to consider in the diagnostic evaluation is the timing of obtaining specimens for definitive testing. It is imperative that diagnostic specimens be obtained in the first 21 days of life and preferably in the first 14 days of life. This is because shedding of CMV in infants aged older than 21 days may reflect perinatal transmission, most commonly from breastfeeding.

Although breast milk-acquired infections are generally of no clinical importance in term babies, this mode of acquisition can complicate the evaluation for cCMV infection. This is a particular concern for infants who fail the newborn hearing screen and requires audiologic referral to investigate for possible etiologies of SNHL. In this setting, infants are often aged older than 3 weeks when they present to an audiologist for diagnostic evaluation. Under these circumstances, a positive urine or saliva PCR for CMV DNA must be interpreted cautiously because a positive result could reflect postnatal acquisition and may have nothing to do with an infant’s hearing loss.

Once diagnostic virology has confirmed the diagnosis, other ancillary studies are important in the evaluation of cCMV (Table 2). The pattern of laboratory abnormalities, if present, is valuable in defining whether an infant has symptomatic or asymptomatic congenital infection. A complete blood count and differential leukocyte count is important, given that thrombocytopenia in the neonate stands out as a predictive biomarker for an increased risk of neurodevelopmental sequelae.

 Liver function tests, including assessment for cholestasis, are useful.

Imaging studies are a key component of the evaluation. Head ultrasound is recommended in the neonatal period and has excellent sensitivity for demonstrating periventricular calcifications, structural lesions, and ventriculomegaly.

 Ophthalmologic evaluation is warranted in all proven cases of cCMV. Serial audiologic assessment is essential, including brainstem auditory evoked responses, in the setting of proven cCMV.

Until universal cCMV screening becomes implemented, which infants require diagnostic evaluation for cCMV infection? Certainly, any infant with signs and symptoms suggestive of cCMV warrants virologic evaluation (Table 1). If CMV is demonstrated, additional studies may be undertaken as outlined earlier. The notion that cCMV is asymptomatic in 85% to 90% of cases, however, may substantially underestimate the frequency of subtle clinical manifestations of infection, because more detailed diagnostic evaluation may not be performed in infants who appear to be unaffected. Newborns who demonstrated prenatal ultrasonographic abnormalities, particularly intrauterine growth retardation, central nervous system (CNS) anomalies, and, in particular, echogenic bowel, should be tested for cCMV in the newborn period. Infants with a small-for-gestational-age presentation or infants born to women who have histologic evidence of placental abnormalities at birth also should be tested for cCMV. The diagnosis of cCMV should be considered in infants with unexplained premature birth because there appears to be a higher CMV birth prevalence in premature infants. Finally, for any newborn whose result is “refer” on the newborn hearing screen, consideration should be given to performing CMV testing prior to hospital discharge.

Although only a small percentage of infants who do not pass the newborn hearing screen actually have hearing loss, there is an enrichment for cCMV in this group of infants.

 Moreover, as previously noted, obtaining a diagnostic specimen for CMV in the immediate newborn period eliminates the diagnostic uncertainty intrinsic to the finding of viral shedding in an infant aged older than 21 days undergoing audiological evaluation. Therefore, I recommend that if an infant does not pass the newborn hearing screen, testing for congenital CMV should be performed immediately in the newborn nursery.

Which infants require treatment for cCMV infection? Currently, treatment is reserved for infants with symptomatic congenital infection; that is, infants with obvious signs (by clinical assessment, laboratory studies, or imaging abnormalities) of disease at birth. Infants with symptomatic disease including the CNS are probably the highest-priority candidates for treatment. This includes infants with microcephaly; radiographic abnormalities consistent with cCMV CNS disease (ventriculomegaly, intracerebral calcifications, periventricular echogenicity, cortical or cerebellar malformations); abnormal cerebrospinal fluid (CSF) indices for age; chorioretinitis; sensorineural hearing loss; or the detection of CMV DNA in CSF.

Infants with clinical evidence of cCMV who have clear-cut symptomatic disease, even without CNS involvement, also should be offered therapy given that the risk of long-term neurodevelopmental sequelae is high.

This includes infants with thrombocytopenia, petechiae, hepatomegaly, splenomegaly, intrauterine growth restriction, hepatitis (raised transaminases or bilirubin), or other signs of infection. Those infants who have isolated SNHL with no other clinical manifestation of infection and those with asymptomatic congenital infection are not currently considered candidates for antiviral therapy, however, although the potential benefits of treatment are being evaluated in several active clinical trials and consultation with an expert is recommended.

Treatment, when indicated, should consist of oral valganciclovir suspension. The suggested dose is 16 mg/kg orally twice daily. In infants unable to tolerate oral therapy, intravenous therapy with ganciclovir can be considered. Treatment should be commenced in the first month of life. The finding of CMV by PCR or culture in urine, saliva, or blood in an infant aged older than 21 days cannot be presumed to be diagnostic of cCMV infection because breastfed babies, as noted above, may acquire infection postnatally.

 This confounds the interpretation of diagnostic studies in infants who have clinical features of congenital infection.

) will perform CMV DNA PCR on saved, archived newborn dried blood spots if available (routinely obtained in the course of normal newborn care and retained in most states), with permission of the infant’s family and the respective state health department. Clinicians interested in this service can contact the lab for further discussion. In some cases, the test helps resolve the question of whether an infant was born with cCMV infection.

Active clinical studies are also examining whether delayed initiation of antiviral therapy (ie, beyond age 1 month) is beneficial. These studies, in particular, are being pursued in infants with previously unexplained SNHL that is recognized later in infancy or early childhood to be attributed to cCMV. Again, consultation with a pediatric infectious disease specialist is recommended in this circumstance.

Evidence of benefit conferred by therapy with oral valganciclovir was demonstrated in a randomized, placebo-controlled trial that showed a statistically significant benefit of treatment in symptomatic neonates.

 All symptomatic cytomegalovirus-infected neonates received valganciclovir for 6 weeks and were then randomized to receive either placebo or additional valganciclovir treatment to complete a 6-month course. Neonates receiving 6 months of valganciclovir had an increased likelihood of improved hearing at 24 months versus those who received only 6 weeks of valganciclovir treatment (followed by placebo). Importantly, neurodevelopmental outcomes also were improved with therapy.

 Based on these data, antiviral therapy with valganciclovir should be considered in all infants with symptomatic cCMV infection.

Laboratory monitoring is essential in infants treated with valganciclovir. Treatment is associated with neutropenia, and absolute neutrophil counts should be followed weekly for 6 to 8 weeks, then monthly for the duration of therapy. Transaminases should be followed monthly throughout therapy. For infants with drug-induced neutropenia, although there are no consensus management guidelines on this issue, therapy with G-CSF can be offered as needed. This allows many infants to complete a full 6-month course of treatment.

Many parents and clinicians become invested in their commitment to finish a 6-month course of therapy, and G-CSF can safely enable this. The author also recommends that audiologic testing be done at 3-month intervals for the first 3 years of life in all cases of cCMV, irrespective of whether symptoms are present at birth or whether the infant is treated with valganciclovir, and, at a minimum, annually thereafter through adolescence (ages 10 to 19 years).

Serial developmental assessments, beginning at the first year of life, are helpful in some children with symptomatic cCMV disease, as is additional neuroimaging. Because some infants with cCMV with evolving SNHL are or become candidates for cochlear implantation, brain magnetic resonance imaging (MRI) can be considered at the same time that temporal bone MRI is performed prior to implant placement.

Treatment and monitoring of cCMV involves much more than just antiviral therapy and monitoring for drug toxicity. It requires a coordinated, team-based approach including, in many instances, specialists in ophthalmology, audiology, otolaryngology, neurology, developmental pediatrics, occupational and physical therapy, orthopedic surgeons, physiatrists, and pediatric infectious disease specialists. The pediatrician can play a central role in coordinating and managing the multidisciplinary evaluations required by many of these infants.

Finally, the infant with cCMV can and should receive routine childhood immunizations, including infants on antiviral therapy, given that there is no evidence such infants have overarching immune deficiencies or problems handling live-virus vaccines.

Infants with asymptomatic cCMV are at risk for long-term sequelae, in particular SNHL. Thus, there has been considerable interest in universal newborn CMV screening, and, in particular, the question of whether cCMV should be added to the Recommended Uniform Screening Panel (RUSP; 

www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html

), which is recommended for all newborns.

Two major issues have so far precluded adding cCMV to the RUSP panel. First, it is not yet clear what constitutes the optimal specimen for newborn screening for CMV infection. Performing PCR for CMV DNA on the dried newborn blood spot would, in principle, represent an ideal strategy given that it is obtained routinely in the nursery. Therefore, using the blood spot for this purpose would obviate the need for procuring additional samples for CMV testing. However, a multicenter cCMV screening study of blood spot PCR demonstrated suboptimal sensitivity.

 Alternative approaches could include PCR testing of saliva or urine samples, but the cost associated with obtaining such samples in all newborns may be prohibitive.

Second, in contrast to most newborn screening tests (which are typically performed to identify uniformly serious and even life-threatening conditions), cCMV screening will identify many infants who are destined to have a normal clinical outcome. On the other hand, advocates for universal cCMV screening point out that even asymptomatic congenitally infected infants are at risk for development of SNHL, even if they pass the newborn hearing screen, and that identification of such infants is not only capable of improving their clinical outcomes but is also cost-effective.

 Further study is required to resolve this issue.

A compromise that has emerged in some states is “targeted screening,” that is, testing for cCMV in all infants who fail the newborn hearing screen. Such programs will miss the majority of cases of cCMV but will facilitate timely diagnosis and early intervention for many infants who could benefit from intervention.

 An exciting development has been the engagement of state legislative bodies across the United States addressing the issue of targeted screening. Several bills have been passed in recent years that variably mandate targeted screening and/or require state health departments to provide educational resources, aimed in particular at healthcare providers and young women of childbearing age, about the problem of cCMV infection (Figure).

For example, a CMV knowledge and awareness bill, the Vivian Act, is currently under consideration by the state of Minnesota House of Representatives (

www.house.leg.state.mn.us/members/pressrelease.asp?pressid=28204&party=2&memid=15434

). It is hoped that these measures can address the substantial and disconcerting knowledge deficit that exists, both among the lay public and among physicians, regarding the risks of acquiring CMV infections during pregnancy.

 In fact, such legislation could have a significant impact on future cCMV infections given that education about simple hygienic precautions women can take to avoid infection has been shown in other studies to be effective in preventing acquisition of CMV during pregnancy.

Ultimately, prevention of cCMV will most likely require the development and implementation of an effective vaccine. Several CMV vaccine platforms have been developed and assessed in preclinical models, and in phase 1 and phase 2 human studies.

 The best-studied candidate to date, a purified and adjuvanted recombinant vaccine against the immunodominant glycoprotein B present in the CMV viral envelope, has demonstrated efficacy ranging from 43% to 50% in preventing primary CMV infection in young women.

Many questions remain about how a CMV vaccine would be used in clinical practice. Should a CMV vaccine be given universally to young children toward the goal of universal coverage (“herd” immunity), using a paradigm that was successful for vaccine-mediated protection against congenital rubella syndrome? Or, should a vaccine selectively target young women (and young men) of children-bearing age to enhance protection during the childbearing years? Should serologic screening be performed before the administration of vaccine to young women, knowing that the greatest risk for disability in infants occurs in the context of primary maternal infection during pregnancy? Or, should all women be vaccinated prior to pregnancy, irrespective of CMV serology results, given that it is becoming clear that CMV “immune” women can become reinfected with new strains during pregnancy that can result in congenital transmission? Although reinfection probably results in fewer sequelae than does primary maternal infection during pregnancy,

 a strong case can be made for universal immunization of women of childbearing age, since “boosting” natural immunity may prove useful in preventing reinfections.

Regardless of how these questions play out, these are exciting times with encouraging prospects ahead for solving the problem of cCMV. The combination effects of increased awareness, evolution of newborn screening programs, and development and deployment of an effective vaccine should synergize on the near horizon to give clinicians the solutions for this common, underrecognized, and disabling infection in newborns.

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https://www.healthypeople.gov/2020/topics-objectives/topic/social-determinants-of-health

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