The apparent paradox of maternal seropositivity as a risk factor for congenital cytomegalovirus infection: a population‐based prediction model

Abstract

Because maternal seropositivity for CMV is associated with substantial protection against congenital CMV infection, prevention measures have focused mainly on seronegative pregnant women for decades. However, population-wide insight in the contribution of nonprimary infection (reactivation and/or re-infection with a different strain) on the most common sequela, hearing loss, is missing. A population-based prediction model was developed to estimate the proportion of congenital CMV-related hearing loss resulting from nonprimary maternal infection. Incorporated was a meta-analysis of the risk of hearing loss, calculating pooled proportions of children with hearing loss after nonprimary and primary infection. Subsequently, the model was applied for worldwide present population seroprevalences (range 30-95%). It was estimated that, for all population seroprevalences, nonprimary maternal infections are responsible for the majority of congenital CMV infections. This proportion increased with seroprevalence, ranging from 57% (95%CI 24-85%) to 96% (95% CI 88-99%) for seroprevalences of 30% to 95%. Our meta-analysis (six reports) showed that the risk of hearing loss after nonprimary infection was 11% (28/253 children, 95% CI 7-15%) versus 13% (50/385 children, 95% CI 10-16%) after primary infection. Incorporating this risk into our model, we estimated that nonprimary infections also accounted for the majority of CMV-related hearing loss. This proportion ranged from 53% (95% CI 13-86%) to 95% (95% CI 62-99%) for seroprevalences of 30% to 95%. Our data underline the worldwide contribution of nonprimary infections in causing CMV-related hearing loss. These results imply that prevention research such as vaccine and hygiene studies should not only be directed at seronegative but also seropositive pregnant women.

Hearing Loss and Congenital CMV Infection: A Systematic Review

“…The increased rate of nonprimary infections leads to a higher birth prevalence on population level, despite the lower risk of vertical transmission. 12,30 The risk of symptomatic infection and permanent sequelae is higher among infants whose mothers experienced a primary infection, but disabilities have also been observed as a result of nonprimary infection. 27,87,88 Percentages of newborns with symptomatic disease or long-term sequelae after nonprimary infection vary between 1% and 10%.…”

“…20,21 In seropositive mothers, reactivation of a latent virus or reinfection with a new CMV strain can cause cCMV disease as well, with or without permanent sequelae. [22][23][24][25][26][27][28][29][30] The risk of vertical transmission seems to be higher in primary infections than in nonprimary infections. In a meta-analysis, Kenneson and Cannon 12 found rates of vertical transmission of 32% and 1.4% for primary and nonprimary infections, respectively.…”

Congenital Human Cytomegalovirus Infection and the Enigma of Maternal Immunity

“…Findings from this study strongly suggest that providing natural immunity to HCMV by early exposure to HCMV or by prophylactic vaccines that induce immunity as measured by surrogate assays of naturally acquired immunity to HCMV would have little impact on the prevalence of congenital HCMV infections. Modeling of the impact of maternal HCMV immunity on the natural history of congenital HCMV infection has also suggested a limited role of maternal immunity, as measured by current surrogates of protective immunity, in the modification of the natural history of congenital HCMV infections (43). As was noted earlier, the rate of congenital HCMV infections continues to increase as the rates of maternal seroimmunity increase, an epidemiology that is in direct contrast to that observed for rubella virus infections in that the incidence of congenital rubella virus infection falls as the rate of maternal rubella immunity increases (25,(44)(45)(46).…”

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

“…Increasingly, it is also recognized that HCMV seronegative women are not the only group that are at risk during pregnancy-reactivation in HCMV seropositive carriers can also be a source of virus transmission to the foetus during pregnancy. 82 Similarly, there are data which suggest that subclinical HCMV infection may be associated with long-term diseases, such as atherosclerosis, chronic graft rejection and neoplasias-where, clearly, reactivation is likely to be a major source of infectious virus. 83 The transplant setting Following solid organ transplantation (e.g., liver, kidney, heart or lung), transfer of latent HCMV in the graft from a seropositive donor (D 1 ) to a seronegative recipient (R 2 ) frequently leads to serious HCMV disease in these patients who are also receiving immunosuppressive treatments.…”

“…The incidence of congenital HCMV infection does, however, correlate with HCMV seroprevelance. 82,[88][89][90] Consequently, non-primary infections caused by either re-infection of, or reactivation in, HCMV seropositive mothers are also likely to be a cause of congenital infection, despite preformed HCMV-specific maternal antibodies. Although the relative contribution of virus reactivation or reinfection to congenital infections is not clear, 91 prevention of infection in either scenario would be beneficial.…”