Long-Term Sequelae of Congenital Cytomegalovirus Infection are Limited to Maternal Infection in the First Trimester of Pregnancy

Abstract

Context: Congenital CMV (cCMV) infection is a major cause of sensorineural and neurological disabilities. The aim of the study was to revisit the relationship between gestational age at maternal primary infection and outcome in recent cases (2011-2017) prospectively assessed with accurate virological tools. Methods: Women with a primary infection in pregnancy and an infected fetus and/or an infected child aged at least 1 year at the time of analysis were included prospectively. Accurate determination of the timing of maternal primary infection was based upon serial measurement of a combination of IgM, IgG, IgG-avidity in sera collected in the first, second and third trimester of pregnancy. Assessment of infected children was done according to a structured follow-up from birth up until 48 months. Findings: 255 women/fetus or child pairs were included between 2011 and 2017. Dating of maternal infection was done prospectively in 86% of cases and retrospectively in 14%. At a median follow-up of 24 months, hearing loss and/or neurologic sequelae were seen in 18.2% (35/192) of infected children. The rate of long-term sequelae was 32.4% (35/108) in children infected after a maternal primary infection in the first trimester and 0 (0/79) in children infected after a maternal infection of the second or third trimester (p<.0001). Interpretation: These results suggest that CMV fetal infection is severe only when the virus hits the fetus in the embryonic or early fetal period. Women with seroconversion in the second or third trimester should be reassured on the outcome of fetal infection. Babies infected after maternal primary-infection in the second or third trimester do not need audiological or specialized neurological follow-up. Clinical Trial Number: Cymeval II and Cymepedia Clinicaltrial.gov numbers, NCT01651585 and NCT01923636. Funding Statement: This work was funded by the French government (Direction de la recherche Clinique et Developpement). Declaration of Interests: M.L-V. declares receiving financial support for meeting expenses from BioMerieux outside the submitted work. The remaining authors report no conflict of interest. Ethics Approval Statement: The cohort was built by pooling cCMV cases from 3 different studies which have included patients between 2011 and 2017. The Cymeval II study (11), the Cymepedia study (12) and the BiocCMV study. Ethics committee approved the 3 studies (2011-001610-34; 2013-A00213-42; 2016-14024) and written informed consent was obtained before inclusion. Cymeval II and Cymepedia studies are multicentre studies with 13 recruiting French centers, BiocCMV is a monocentric study in Necker Hospital.