Research Article: Identification of Symptomatic Fetuses Infected with Cytomegalovirus Using Amniotic Fluid Peptide Biomarkers

Date Published: January 25, 2016

Publisher: Public Library of Science

Author(s): Cyrille Desveaux, Julie Klein, Marianne Leruez-Ville, Adela Ramirez-Torres, Chrystelle Lacroix, Benjamin Breuil, Carine Froment, Jean-Loup Bascands, Joost P. Schanstra, Yves Ville, Sallie R. Permar.


Cytomegalovirus (CMV) is the most common cause of congenital infection, and is a major cause of sensorineural hearing loss and neurological disabilities. Evaluating the risk for a CMV infected fetus to develop severe clinical symptoms after birth is crucial to provide appropriate guidance to pregnant women who might have to consider termination of pregnancy or experimental prenatal medical therapies. However, establishing the prognosis before birth remains a challenge. This evaluation is currently based upon fetal imaging and fetal biological parameters, but the positive and negative predictive values of these parameters are not optimal, leaving room for the development of new prognostic factors. Here, we compared the amniotic fluid peptidome between asymptomatic fetuses who were born as asymptomatic neonates and symptomatic fetuses who were either terminated in view of severe cerebral lesions or born as severely symptomatic neonates. This comparison allowed us to identify a 34-peptide classifier in a discovery cohort of 13 symptomatic and 13 asymptomatic neonates. This classifier further yielded 89% sensitivity, 75% specificity and an area under the curve of 0.90 to segregate 9 severely symptomatic from 12 asymptomatic neonates in a validation cohort, showing an overall better performance than that of classical fetal laboratory parameters. Pathway analysis of the 34 peptides underlined the role of viral entry in fetuses with severe brain disease as well as the potential importance of both beta-2-microglobulin and adiponectin to protect the injured fetal brain infected with CMV. The results also suggested the mechanistic implication of the T calcium channel alpha-1G (CACNA1G) protein in the development of seizures in severely CMV infected children. These results open a new field for potential therapeutic options. In conclusion, this study demonstrates that amniotic fluid peptidome analysis can effectively predict the severity of congenital CMV infection. This peptidomic classifier may therefore be used in clinical settings during pregnancy to improve prenatal counseling.

Partial Text

Cytomegalovirus (CMV) is the most common cause of congenital infection with an incidence of 0.7% at birth [1]. Congenital CMV infection is the leading cause of non-genetic hearing loss and the most frequent viral cause of neurodevelopmental delay. Primary maternal CMV infection in pregnancy carries a 30% to 40% risk of vertical transplacental transmission, and 10% of those infected fetuses will be born as infected infants with clinical symptoms and long-term disabilities including sensorineural hearing loss and cognitive deficits such as mental retardation, cerebral palsy or seizures [2]. In addition, 5 to 10% of asymptomatic infants will develop milder forms of sensorineural hearing loss and of psychomotor delay later in life [2].

The management of fetal CMV infection remains controversial. One difficulty is to establish the prognosis timely and accurately before birth. Prognostic factors are mainly derived from prenatal ultrasound or MRI imaging of the fetal brain and these can either appear late in the pregnancy and/or be objectified only after birth. Laboratory markers of the severity of infection including thrombocytopenia and high serum levels of beta-2-microglobulin in fetal blood have been suggested to precede the development of brain lesions. These can be obtained following cordocentesis, another invasive procedure performed under ultrasound guidance and separate from the amniocentesis performed for diagnosis [8,9,26]. We therefore aimed at identifying reliable protein-based prognostic factors of fetal CMV infection in the amniotic fluid at the time of prenatal diagnosis by amniocentesis.




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