Congenital Cytomegalovirus Infection: Management Update

Asma Khalil; Chrissie Jones; Yves Villec

Disclosures

Curr Opin Infect Dis. 2017;30(3):274-280. 

In This Article

Prenatal Diagnosis and Prognosis

Diagnosis of CMV infection in pregnancy is based on measurement of CMV-specific immunoglobulin G and immunoglobulin M in the maternal blood. The presence of immunoglobulin M is not diagnostic of recent primary CMV infection as immunoglobulin M may persist for many months after the primary infection. Immunoglobulin M may also be detected during a secondary infection, and there may be cross-reactivity with immunoglobulin M because of another viral infection, for example, Epstein–Barr virus. Finally, immunoglobulin M may be detected as a result of nonspecific polyclonal stimulation of the immune system. Immunoglobulin G avidity testing is, therefore, often used to better define the timing of the infection (i.e., before or during pregnancy). Avidity levels are quantified by the avidity index which describes the proportion of immunoglobulin G bound to the antigen following treatment with denaturing agents.[17] In general, a high avidity index (greater than 60%) is highly suggestive of past (greater than 3 months earlier) or secondary infection, whereas a low avidity index (less than 30%) is highly suggestive of recent primary infection (i.e., within the past 3 months).[18] Maternal viremia is a useful adjunct when suspecting seroconversion at 12 weeks.[19] Diagnosis of secondary CMV infection can be difficult. A rise in immunoglobulin G levels does not confirm secondary infection as this rise may be because of nonspecific polyclonal stimulation of the immune system. In practice, therefore, the only way of confirming secondary CMV infection is by invasive testing.

Diagnosis of fetal infection is made by identification of the viral genome (DNA) by PCR, generally real-time PCR, in the amniotic fluid following amniocentesis. Virus isolation has a higher specificity but lower sensitivity than PCR and is now rarely used. Depending on the virological method used, sensitivity ranges between 75 and 100%, with specificity between 67 and 100%.[17,20–23] Amniocentesis should not be performed before 20 weeks' gestation when fetal urination is well established. Furthermore, following primary maternal infection, the infective process will not lead to CMV excretion in the fetal urine until an average of 6–8 weeks later;[24] for this reason amniocentesis should be delayed until this point. In fact, most false-negative amniocentesis results are likely to be attributed to the amniotic fluid being sampled too early in pregnancy or too early after the primary infection, and some studies suggest that when sampling conditions are ideal, the sensitivity of prenatal diagnosis by PCR is close to 100%.[24] Occasionally false negatives may be explained by late transmission of the virus. One study found that 8% of neonates with negative amniocentesis showed viral excretion at birth;[25] however, on follow-up none developed any sequelae. Because of the small risk of false positive and false-negative PCR amniocentesis results, neonatal testing to confirm the diagnosis is essential.[26,27]

Following prenatal diagnosis of fetal CMV infection, the main aim is to predict the risk of symptomatic neonatal infection, which is associated with poor outcome. Accurate prenatal prediction of poor prognosis for affected infants has proved challenging; estimates are based largely on three factors: timing of the infection; presence and type of fetal abnormalities; laboratory parameters. It appears that, in common with other viral infections, the risk of vertical transmission increases with gestation. However, the association between the timing of infection and severity of fetal/neonatal outcome is less well defined. As the diagnosis of congenital CMV infection is often incidental, severe ultrasound abnormalities are described more often than subtle findings. Ultrasound findings can be categorized as fetal cranial, fetal extracranial, and placenta/amniotic fluid abnormalities. It appears that the main sonographic prognostic indicator is fetal cerebral abnormalities.[28] Farkas et al.[28] reported that if the antenatal ultrasound examination of the fetal brain was normal, then normal early neuropsychological outcome was likely. When both ultrasound and MRI of the fetal brain are normal prenatally, the neonatal outcome is generally good.[29] The combined predictive value of a normal ultrasound and MRI evaluation to predict an asymptomatic neonate, in fetuses with a positive amniocentesis and when imaging was performed up to the third trimester, after 30 weeks, is at best 95%.[30] Fetal laboratory findings, including viral load, thrombocytopenia (platelet count <100 000/μl) and raised alanine aminotransferase (>80 IU/ml) in the fetal blood may bridge this 5% gap.

In a recent study the risk assessment of infected fetuses for being symptomatic at birth has been shown to be possible as early as the time of diagnosis; ultrasound abnormalities and either amniotic fluid viral load or fetal blood profile (viral load and platelet count) were independent prognostic factors of symptomatic congenital CMV at birth.[31] Both fetal platelet count and blood viral load were better predictors than amniotic fluid viral load. The combined negative predictive values of ultrasound and viral load in amniotic fluid and that of ultrasound and fetal blood parameters were 95–100%, respectively.[31] Interestingly, when investigating the nonsevere ultrasound features, the positive predictive values of ultrasound alone and in combination with amniotic fluid viral load or with fetal blood parameters were 60, 78, and 79%, respectively.[31]

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