Significance Studies have suggested that primary human cytomegalovirus (CMV) infection early in gestation increases the likelihood of fetal disease when compared to infection later in gestation. It is possible that this difference is due to a combination of fetal neurodevelopmental processes and placental maturational changes related to transport of maternal antibodies during the course of gestation. This implies that fetal infection early in gestation in the absence of a threshold level of protective maternal antibodies could increase the risk for infection and damage, whereas susceptibility decreases later in gestation as a result of increased efficiency of transplacental transfer of protective maternal antibodies. Objectives Recent evidence suggests that transfer of maternal rhesus IgG begins prior to the second trimester and accelerates during gestation such that fetal IgG levels are equivalent to maternal levels near term. Studies were carried out to address how the timing of fetal CMV infection during gestation can alter pathologic outcome. Results Fetuses were inoculated in utero via ultrasound-guidance using varying titers of rhesus CMV in the late first trimester, and compared to fetuses inoculated in the early second trimester. Studies showed a developmental window of susceptibility to CMV-induced disease. All fetuses inoculated in the second trimester were grossly normal when delivered near term, whereas fetuses inoculated in the late first trimester displayed severe CMV disease (intrauterine growth restriction, ventriculomegaly, microcephaly, cardiac and musculoskeletal abnormalities). These results strongly implicate the timing of transplacental transfer of maternal IgG in altering the course of viral replication and pathologic outcome. Future Directions Studies will focus on the postnatal complications of prenatal exposure, with an emphasis on neurologic, hematologic, and immunologic endpoints. KEYWORDS cytomegalovirus, fetus, growth, neuropathology, pathogenesis, IgG
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