The "silent" global burden of congenital cytomegalovirus

Abstract

Human cytomegalovirus (CMV) is a leading cause of congenital infections worldwide. In the developed world, following the virtual elimination of circulating rubella, it is the commonest nongenetic cause of childhood hearing loss and an important cause of neurodevelopmental delay. The seroprevalence of CMV in adults and the incidence of congenital CMV infection are highest in developing countries (1 to 5% of births) and are most likely driven by nonprimary maternal infections. However, reliable estimates of prevalence and outcome from developing countries are not available. This is largely due to the dogma that maternal preexisting seroimmunity virtually eliminates the risk for sequelae. However, recent data demonstrating similar rates of sequelae, especially hearing loss, following primary and nonprimary maternal infection have underscored the importance of congenital CMV infection in resource-poor settings. Although a significant proportion of congenital CMV infections are attributable to maternal primary infection in well-resourced settings, the absence of specific interventions for seronegative mothers and uncertainty about fetal prognosis have discouraged routine maternal antibody screening. Despite these challenges, encouraging results from prototype vaccines have been reported, and the first randomized phase III trials of prenatal interventions and prolonged postnatal antiviral therapy are under way. Successful implementation of strategies to prevent or reduce the burden of congenital CMV infection will require heightened global awareness among clinicians and the general population. In this review, we highlight the global epidemiology of congenital CMV and the implications of growing knowledge in areas of prevention, diagnosis, prognosis, and management for both low (50 to 70%)- and high (>70%)-seroprevalence settings.

Figures

Fig 1

Estimates of the prevalence of congenital CMV infection and sequelae in infected children in high (90%)- and low (50%)-seroprevalence settings. The following assumptions are made: the risk of primary infection is 2% in both settings, and the risk of intrauterine transmission is 40% during primary infection and 1% in CMV-seropositive mothers. The rates of sequelae are based on estimates from a systematic review of study populations from high-income countries with a range of maternal seroprevalence and congenital infection identified through universal screening (44). Proportions with each category of sequelae do not correspond to 100% because a child may have more than one complication. The figure does not take into account the effect of HIV infection in maternal populations, which would be expected to increase the risk of CMV vertical transmission and sequelae in infected infants. It also does not account for differences in congenital transmission rates observed in mothers of different racial or ethnic backgrounds. *, most of the children in the asymptomatic group will have hearing loss, and there are insufficient data to accurately estimate the number of children with cognitive/motor deficits and vision impairment.

Fig 2

Worldwide CMV seroprevalence rates among women of reproductive age and birth prevalence of congenital CMV infection. For CMV seroprevalences (shaded), percentages were obtained by adding the number of seropositive women from all studies within a given country and dividing that number by the total number of women tested. Reproductive age was generally defined as between 12 and 49 years of age. To reduce sampling variability, only countries that had at least 500 women tested were included. Studies were from Australia, Belgium, Brazil, Canada, Chile, England, Finland, France, Germany, Ghana, India, Israel, Italy, Japan, Scotland, South Africa, Spain, Sweden, Taiwan, Turkey, and the United States (26). For congenital CMV birth prevalences (circles), percentages were obtained from studies with a representative sample size (at least 1,000 newborns). To reduce detection bias, only studies using PCR or culture on saliva or urine were included, with the exception of Netherlands and Portugal, which tested DBS samples by PCR. When more than one representative study was available, percentages were obtained by adding the number of congenitally infected newborns from all studies within a given country and dividing that number by the total number of newborns tested. Countries for which maternal seroprevalence rates and birth prevalence of congenital CMV infection data were available are Brazil, Canada, England, India, Israel, Italy, Japan, Sweden, and the United States. (Adapted from reference .)

Fig 3

Graph representing the risk of intrauterine CMV transmission following maternal primary infection from 15 studies. The transmission risk is the proportion of mothers undergoing a primary infection in a given trimester and/or the preconception period who transmitted CMV to the fetus. The risk is therefore uniform (represented by a flat line) for the time period defined as preconception (from 12 or more weeks prior to conception), first trimester (up to the 12th gestational week), second trimester (from 12 to 26 weeks), and third trimester (26 weeks to delivery) in each of the studies. Studies were grouped according to the number of weeks for which data were collected and are represented by lines of different colors: yellow, studies with late-gestation data; green, studies with preconception and/or first-trimester data; red, studies with first-, second-, and third-trimester data; blue, studies with preconception and first-, second-, and third-trimester data. The black dotted line represents pooling of the data (excluding unpublished data) for each gestational week. The denominator is the sum of mothers undergoing a primary infection from studies with data available for a particular gestational week. The numerator is the total number of transmitter mothers across these studies for that gestational week. Risks are shown as percentages. The number of women undergoing a primary infection in each study is shown in parentheses. (See references , , , , , , , , , , , , , and .)

Fig 4

Proposed diagnostic and management algorithm for maternal and congenital CMV infection. The presence of high-avidity CMV IgG antibodies before 16 weeks of gestation excludes primary infection; however, nonprimary infection is still a possibility. Indications for prenatal testing in nonprimary infections are less clear, and decisions should be made on case-by-case basis when sonographic findings are suggestive of congenital infection. Baseline investigations for newborns with symptomatic congenital CMV infection should include complete blood count, liver function tests, CMV real-time PCR (blood and urine), audiometry, ophthalmology screen, and cranial US/CT/MRI. A low CMV DNA blood viral load in the first month of life can predict a normal development in asymptomatic newborns. Since the cutoff values for amniotic fluid viral load measurements were derived from a few studies and have not been validated with international standards, they may not be generalizable.