Predicting Outcomes of Congenital Cytomegalovirus Infection

By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

SYNOPSIS: Congenital cytomegalovirus infection can cause hearing loss and neurologic deficits, but most affected newborns escape without sequelae. New data suggest a good prognosis if the mother’s infection was after the first trimester and if the newborn has normal hearing, a normal platelet count, and a normal head ultrasound exam.

SOURCE: Fourgeaud J, Magny JF, Couderc S, et al. Predictors of the outcome at 2 years in neonates with congenital cytomegalovirus infection. Pediatrics 2024;153:e2023063531.

Worldwide, approximately 0.7% of newborns are affected by congenital cytomegalovirus (CMV) infection. One in five affected infants develop long-term sequelae, such as sensorineural hearing loss and motor and/or intellectual impairment. Careful follow-up and early intervention can help adversely affected infants, but overevaluation is costly in terms of financial expense and family anxiety. It would be helpful to have a way to identify CMV-infected newborns who are truly at risk of sequelae and to focus ongoing medical care on the infants who are most likely to benefit from additional intervention.

Wanting to determine how best to identify newborns at risk of sequelae of congenital CMV who might be amenable to helpful monitoring and early intervention, Fourgeaud and colleagues in France followed infants born with congenital CMV infection through the first two years of life with a detailed battery of tests along the way. Study subjects were diagnosed to have CMV during the first 10 days of life and were recruited from 13 different hospitals throughout France.

Of 227 babies followed to the completion of this study, 43 (19%) had serious sequelae of congenital CMV infection at 24 months of age. The mothers of 50% of the studied babies had had CMV infection during the first trimester of pregnancy, but 93% of babies with sequelae of CMV infection at 2 years of age were born to mothers with CMV during the first trimester.

Of the 43 babies with CMV sequelae at 2 years of age, 86% had abnormal findings consistent with CMV in the initial days of life (as opposed to 40% of those who would not have residual symptoms at 2 years of age). Congenitally evident hearing loss, splenomegaly, hypotonia, petechiae, and respiratory distress were all more common in children who would have sequelae persisting until 2 years of age. Thrombocytopenia and abnormal cranial ultrasonography during the initial weeks of life also were more common in babies who would experience chronic sequelae of CMV.

The strongest predictor of chronic sequelae of CMV was the mother being infected during the first trimester. No child whose mother had second- or third-trimester CMV infection went on to have sensorineural hearing loss, and only a couple had other neurologic sequelae attributable to CMV.

CMV-infected babies with congenital sensorineural hearing loss never recovered from that hearing loss. Thus, hearing loss evident in the first weeks of life was a strong clinical predictor of persistent sequelae at 2 years of age. Abnormal cranial ultrasound during the neonatal period was an additional strong predictor of sequelae at 2 years of age.

Looking positively, the presence during the neonatal period of normal hearing, a normal platelet count, and normal cranial ultrasonography were highly predictive (98% specificity, 93% negative predictive value, and 91% positive predictive value) of an absence of CMV sequelae at 2 years of age. The authors suggest that children born to mothers without a first-trimester CMV infection and children with neither neonatal sensorineural hearing loss nor thrombocytopenia nor an abnormal cranial ultrasound can be followed less aggressively and with less concern than should be other CMV-affected newborns. In this way, the majority of CMV-infected newborns would receive appropriate reassurance. The authors also found no evidence to suggest treatment of congenital CMV beyond that which was recommended in 2017 (valganciclovir use for six months limited to infected neonates with moderate to severe symptomatic disease).¹

COMMENTARY

CMV is ubiquitous.² Congenital CMV infection is more common than any other congenital infection, and it is the most common non-genetic cause of congenital sensorineural hearing loss.³ Seropositivity does not prevent a pregnant woman from transmitting CMV to her pre-born child, and most severe congenital infections are due to non-primary maternal infections.³ Approximately 90% of babies born with congenital CMV infection are asymptomatic; approximately half of newborns with symptomatic congenital CMV infection do not go on to have persisting sequelae.³ In addition to babies with vertically transmitted congenital CMV, premature babies and immunocompromised hosts can have poor outcomes due to CMV.

Newborns with moderate to severe symptomatic congenital CMV infection have improved hearing and neurodevelopmental outcomes if they receive six months of oral valganciclovir.^2,3 By current expert guidelines, newborns with mild symptoms or just sensorineural hearing loss should not receive valganciclovir; treatment is of unproven effectiveness if started after the first month of life.²

The Committee on Infectious Diseases of the American Academy of Pediatrics continuously updates their “Red Book” with infection-related recommendations, including those relevant to the evaluation and management of congenital CMV infection.² Nonetheless, there is significant variation in congenital CMV evaluation and treatment practices among North American pediatric infectious disease specialists.⁴ In addition, some otolaryngologists advocate for more aggressive testing and treatment of congenital CMV than what is advised by the American Academy of Pediatrics.⁴

The seroepidemiology of CMV varies geographically, even within North America.⁵ Current estimates are that 49% of U.S. 18- to 19-year-old females and 42% of U.S. 18- to 19-year-old males are seropositive for CMV, while in Canada, 24% of 18- to 19-year-old females and 14% of 18- to 19-year-old males are seropositive.⁵

Thus, pregnant women are at risk of primary and non-primary CMV infections and, through them, pre-born children are at risk of hearing loss and neurodevelopmental compromise. The new data from Fourgeaud and colleagues add some reassurance that women infected after the first trimester of pregnancy are less likely to deliver adversely affected children, and asymptomatic CMV-infected newborns with normal hearing, normal platelet counts, and normal head ultrasound exams are likely not to have adverse sequelae at 2 years of age. This is reassuring, even if incompletely so, and allows follow-up and treatment resources to be devoted to newborns at greater risk of adverse sequelae.

References

1. 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:e177-e188.
2. Committee on Infectious Diseases, American Academy of Pediatrics. Cytomegalovirus infection. Red Book: 2021–2024 Report of the Committee on Infectious Diseases, 32nd Edition. American Academy of Pediatrics;2024:294-300.
3. Pinninti S, Hough-Telford C, Pati S, Boppana S. Cytomegalovirus and Epstein-Barr virus infections. Pediatr Rev 2016;37:223-234.
4. Hoki C, White M, Pesch MH, et al. A cross-sectional survey of pediatric infectious disease physicians’ approach to congenital cytomgalovirus infection. Int J Neonatal Screen 2023;9:17.
5. Dana Flanders W, Lally C, Dilley A, Diaz-Decaro J. Estimated cytomegalovirus seroprevalence in the general population of the United States and Canada. J Med Virol 2024;96:e29525.