Pitfalls in the Serological Evaluation of Maternal Cytomegalovirus Infection as a Potential Cause of Fetal and Neonatal Involvements: A Narrative Literature Review

Abstract

Cytomegalovirus (CMV) is the most common cause of intrauterine infection and serological assays are the primary tools for assessing CMV infections during pregnancy. CMV-specific immunoglobulin M (IgM) antibodies have been used as a diagnostic marker for primary CMV infection in pregnant women, although CMV-IgM has been detected in non-primary CMV infections. IgG avidity testing may aid the distinguishing of primary from non-primary CMV infection; however, there is no standardized assay for detecting this difference. Moreover, when maternal serology shows positive CMV-IgG with negative CMV-IgM findings, vertical transmission probability following primary CMV infection is often excluded. However, symptomatic congenital CMV infections in the context of negative findings for maternal CMV-IgM have been reported recently. The absence of CMV-IgM is recognized in both primary and non-primary CMV infections. Furthermore, maternal non-primary CMV infections during pregnancy may yield a greater proportion of symptomatic congenital CMV infections than previously thought. If universal prenatal screening is performed, ultrasonography for abnormal fetal findings should be conducted regardless of CMV-IgM antibody status. If not universally screened, CMV antibody screening should be performed whenever routine fetal ultrasound reveals abnormal findings. For suspected fetal CMV infection, amniotic fluid or postnatal infant urine CMV-DNA testing is required.

Congenital Cytomegalovirus and Hearing Loss: The State of the Art

“…Diagnosis of primary CMV infection during pregnancy can be made by detection of CMV IgG seroconversion or CMV IgM positivity associated with low IgG avidity [ 38 ]. Currently, most public health policies and international scientific societies do not routinely recommend universal maternal prenatal screening for CMV infection due to the following reasons [ 30 , 39 , 40 , 41 ]: (a) lack of highly sensitive and specific prenatal tests; (b) CMV serological screening is not applicable to non-primary CMV infection; (c) lack of effective interventions to prevent transmission to the fetus; (d) lack of safe and effective prenatal treatments; (e) inability of laboratory tests to predict which babies will develop long-term neurological and audiological complications; (f) potentially increased rate of unnecessary abortions. Moreover, the false-positive rate would be much higher in the screened population than in women preselected for suspected CMV infection and, as a result, many pregnant women would undergo unnecessary additional testing and invasive procedures [ 39 , 42 ].…”

Serological screening for cytomegalovirus during pregnancy: A systematic review of clinical practice guidelines and consensus statements

“…23,33 Limitations of CMV IgM assays include a narrow detection window, long-term persistence of CMV IgM and false positives. 34 Interpretation of CMV IgG avidity assays can also be difficult as they vary from one laboratory to another. 35 Novel modes of CMV screening are currently being explored, such as detecting viral DNA by re-analysing maternal plasma cell-free DNA obtained for aneuploidy screening.…”

“…One of the key principles for evaluating the suitability of a population‐based screening programme is to have a reliable, reproducible and acceptable test 23,33 . Limitations of CMV IgM assays include a narrow detection window, long‐term persistence of CMV IgM and false positives 34 . Interpretation of CMV IgG avidity assays can also be difficult as they vary from one laboratory to another 35 .…”

Pathogenicity and diagnostic methods of human cytomegalovirus

“…employed alongside IgM detection to distinguish between primary HCMV infection and reinfection. While serology offers a swift method for diagnosing HCMV infection, it is essential to interpret the results accurately due to the elevated occurrence of false positive IgM antibody tests for HCMV (Iijima, 2022). This is particularly notable in patients with concurrent autoantibodies associated with lupus (Cannavan et al, 1998).…”