We found that the strongest predictor of delayed hearing loss was the presence of symptoms at birth. Children who passed initial audiologic examinations but who had CMV-related symptoms at birth (e.g., jaundice, petechiae, microcephaly, etc.) were nearly 6 times more likely to develop hearing loss than children who were asymptomatic at birth.
Another important finding was that longer duration of viral shedding (as measured by age at last culture-positive visit) may be a predictor of delayed hearing loss. This raises the hypothesis that ongoing viral replication could play a role in the development of delayed hearing loss. However, there are no data on whether peripheral CMV shedding is linked to CMV replication in the inner ear. They could occur independently. Furthermore, the measure of viral shedding—age at last positive-culture visit—was an imperfect measure of persistent shedding. Nearly 1/3 of children shed CMV intermittently. Thus, those with older ages at their last positive visit may not have been shedding regularly in the interim, making it less likely that persistent CMV shedding played a role in the development of hearing loss. Finally, the children were not enrolled in studies designed to evaluate the association between viral shedding and delayed hearing loss. As a result, there was wide variation in the number of visits and length of follow-up, complicating the analyses and leading to a relatively small sample for the multivariate analysis. Nevertheless, these complications were minimized by the matching scheme, controlling for confounding, and restriction to children with at least 3 visits and no more than 8 years of follow-up.
Our results differed from a previous study that evaluated persistent CMV shedding and hearing loss. In a smaller study, Noyola et al.17
found that children who shed CMV for a shorter length of time were more likely to have hearing loss and progressive hearing loss. Those study results may differ from ours because Noyola and colleagues did not analyze delayed hearing loss separately, but instead included it in the category of progressive hearing loss. Furthermore, they did not show the ages at which hearing loss occurred, so that one could not determine whether the shorter duration of CMV shedding actually preceded hearing loss in individual children.
Our multivariate analyses suggest that delayed hearing loss may be associated with persistent CMV shedding during childhood. Other factors may also be important. Viral factors that are present in utero (e.g., high viral load in amniotic fluid) or shortly after birth (e.g., high viral load at birth) may be linked to delayed hearing loss. This would be consistent with results showing that ganciclovir treatment in the 6 weeks following birth seems to prevent some delayed or progressive hearing loss among symptomatic children with CNS involvement.13
High CMV viral loads at birth have been associated with clinical abnormalities at birth (i.e.
, symptomatic congenital CMV infection)14,16,19,20
and with hearing loss.14
The effect of persistently high viral loads on delayed hearing loss, however, is not known. For the follow-up visits which constituted our study, we did not have measures of CMV viral load and so were unable to assess this potential association. Localized CMV shedding in the ear might also be a predictor of delayed hearing loss, but is impractical to measure. Nevertheless, some researchers have had success in detecting CMV in perilymph fluid during cochlear implant surgery.21
Alternatively, non-viral factors such as inflammation related to CMV infection could play a role in delayed and progressive hearing loss. Due to lack of data, however, these theories remain speculative. As has been demonstrated previously,6,9
children with congenital CMV infection who are symptomatic at birth but who test normal on hearing exams are at especially high risk of developing delayed hearing loss. Even though their symptoms often did not include serious, central nervous system impairments, these children were approximately 5–6 times more likely to develop delayed hearing loss, indicating that they need regular audiologic monitoring. Nevertheless, asymptomatic children, who also have much higher rates of delayed hearing loss than the general population, should benefit from regular audiologic monitoring as well.7
In this study we were able to calculate rates of the development of delayed hearing loss. Children with normal hearing at 6 months of age developed hearing loss at the rate of nearly 1% per year if they were asymptomatic at birth and over 4% per year if they were symptomatic at birth. Their cumulative risk by age 8 was substantial—6.9% and 33.7% for populations of asymptomatic and symptomatic children, respectively. Cumulative risk of delayed hearing loss may be even higher, since these numbers do not include children whose newborn hearing test was normal but who developed hearing loss within the first 6 months. It is important to note, however, that some of the children will have mild hearing loss (e.g., thresholds <40 dB) which may not reach clinical significance.6
With this large sample of congenitally infected children we were able to confirm several observations about the dynamics of CMV shedding that were observed in smaller studies. First, CMV was found more frequently in urine than in saliva, confirming that, when available, urine is the best specimen for diagnosis of shedding. Others have found that viral loads are also higher in urine than in saliva or blood.22
Second, intermittent CMV shedding is relatively common17
and may be the result of viral reactivation or reinfection with a different strain.23
Third, the frequency of CMV shedding decreases substantially with age,24
indicating that younger children are a key source of infection, and that pregnant women should use careful hygienic precautions when they are exposed to younger children.25