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.
How common is cCMV 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%.1 Congenital infections are even more prevalent in the developing world, with estimates of rates as high as 6.5% in some populations.2 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.3 Rates of cCMV are highest in black infants, making cCMV an example of a disease reflecting health disparities nationally.4-6
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.7 The largest total of US cases of congenital infection with another teratogenic virus, rubella, was in 1969, when 57,686 cases were reported.8 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.9 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.10 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.11 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.12 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.13 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.
When and how to test for cCMV
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.14
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.15
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.16 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.11 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.17,18 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.
When and how to treat cCMV infections
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.11,17
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.11,17 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.
1. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):253-276.
2. Lanzieri TM, Dollard SC, Bialek SR, Grosse SD. Systematic review of the birth prevalence of congenital cytomegalovirus infection in developing countries. Int J Infect Dis. 2014;22:44-48.
3. US Department of Health and Human Services. Office of Disease Prevention and Health Promotion. 2020 Topics and Objectives: Social Determinants of Health. Available at: https://www.healthypeople.gov/2020/topics-objectives/topic/social-determinants-of-health. Updated June 6, 2018. Accessed June 6, 2018.
4. Fowler KB, Boppana SB. Congenital cytomegalovirus infection. Semin Perinatol. 2018;42(3):149-154.
5. Fowler KB, Ross SA, Shimamura M, et al. Racial and ethnic differences in the prevalence of congenital cytomegalovirus infection. J Pediatr. May 18, 2018. Epub ahead of print.
6. Hotez PJ. Neglected infections of poverty in the United States of America. PLoS Negl Trop Dis. 2008;2(6):e256.
7. França GV, Schuler-Faccini L, Oliveira WK, et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet. 2016;388(10047):891-897.
8. Modlin JF, Brandling-Bennett AD, Witte JJ, Campbell CC, Meyers JD. A review of five years’ experience with rubella vaccine in the United States. Pediatrics. 1975;55(1):20-29.
9. Cannon MJ, Westbrook K, Levis D, Schleiss MR, Thackeray R, Pass RF. Awareness of and behaviors related to child-to-mother transmission of cytomegalovirus. Prev Med. 2012;54(5):351-357.
10. Boppana SB, Ross SA, Fowler KB. Congenital cytomegalovirus infection: clinical outcome. Clin Infect Dis. 2013;57(suppl 4):S178-S181.
11. Cheeran MC, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev. 2009;22(1):99-126.
12. Fowler KB. Congenital cytomegalovirus infection: audiologic outcome. Clin Infect Dis. 2013;57(suppl 4):S182-S184.
13. Fowler KB, Dahle AJ, Boppana SB, Pass RF. Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed? J Pediatr. 1999;135(1):60-64.
14. Cardoso ES, Jesus BL, Gomes LG, Sousa SM, Gadelha SR, Marin LJ. The use of saliva as a practical and feasible alternative to urine in large-scale screening for congenital cytomegalovirus infection increases inclusion and detection rates. Rev Soc Bras Med Trop. 2015;48(2):206-207.
15. Schleiss MR. Acquisition of human cytomegalovirus infection in infants via breast milk: natural immunization or cause for concern? Rev Med Virol. 2006;16(2):73-82.
16. Swanson EC, Schleiss MR. Congenital cytomegalovirus infection: new prospects for prevention and therapy. Pediatr Clin North Am. 2013;60(2):335-349.
17. Rawlinson WD, Boppana SB, Fowler KB, et al. Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect Dis. 2017;17(6):e177-e188.
18. Choi KY, Schimmenti LA, Jurek AM, et al. Detection of cytomegalovirus DNA in dried blood spots of Minnesota infants who do not pass newborn hearing screening. Pediatr Infect Dis J. 2009;28(12):1095-1098.
19. Meyer L, Sharon B, Huang TC, et al. Analysis of archived newborn dried blood spots (DBS) identifies congenital cytomegalovirus as a major cause of unexplained pediatric sensorineural hearing loss. Am J Otolaryngol. 2017;38(5):565-570.
20. Kimberlin DW, Jester PM, Sánchez PJ, et al; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015;372(10):933-943.
21. Boppana SB, Ross SA, Novak Z, et al; National Institute on Deafness and Other Communication Disorders CMV and Hearing Multicenter Screening (CHIMES) Study. Dried blood spot real-time polymerase chain reaction assays to screen newborns for congenital cytomegalovirus infection. JAMA. 2010;303(14):1375-1382.
22. Gantt S, Dionne F, Kozak FK, et al. Cost-effectiveness of universal and targeted newborn screening for congenital cytomegalovirus infection. JAMA Pediatr. 2016;170(12):1173-1180.
23. Ronchi A, Shimamura M, Malhotra PS, Sánchez PJ. Encouraging postnatal cytomegalovirus (CMV) screening: the time is NOW for universal screening! Expert Rev Anti Infect Ther. 2017;15(5):417-419.
24. Diener ML, Zick CD, McVicar SB, Boettger J, Park AH. Outcomes from a hearing-targeted cytomegalovirus screening program. Pediatrics. 2017;139(2):e20160789.
25. Thackeray R, Magnusson BM. Women’s attitudes toward practicing cytomegalovirus prevention behaviors. Prev Med Rep. 2016;4:517-524.
26. Vauloup-Fellous C, Picone O, Cordier AG, et al. Does hygiene counseling have an impact on the rate of CMV primary infection during pregnancy? Results of a 3-year prospective study in a French hospital. J Clin Virol. 2009;46(suppl 4):S49-S53.
27. Schleiss MR, Permar SR, Plotkin SA. Progress toward development of a vaccine against congenital cytomegalovirus infection. Clin Vaccine Immunol. 2017;24(12):e00268-17.
28. Pass RF, Zhang C, Evans A, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med. 2009;360(12):1191-1199.
29. Bernstein DI, Munoz FM, Callahan ST, et al. Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: a randomized clinical trial. Vaccine. 2016;34(3):313-319.
30. Permar SR, Schleiss MR, Plotkin SA. Advancing our understanding of protective maternal immunity as a guide for development of vaccines to reduce congenital cytomegalovirus infections. J Virol. 2018;92(7):e00030-18.