Introduction

Cytomegalovirus (CMV) is the most common perinatal viral infection leading to neonatal and childhood sequelae. Diagnosis of primary maternal CMV infection now frequently involves IgG avidity testing, a sensitive marker of primary CMV infection within the last 4 months.

Recently, a European trial was published assessing antenatal CMV hyperimmune globulin (HIG) use to prevent neonatal infection, and the authors found no difference to treatment, and there were a number of adverse events reported in those receiving CMV HIG. The purpose of this document is to review diagnosis of primary maternal CMV infection, diagnosis of fetal CMV infection, and whether antenatal therapy is warranted.

What is the epidemiology of CMV?

Congenital CMV, a herpesvirus, is the most common viral infection of the fetus and is the leading nongenetic cause of congenital deafness, affecting nearly 40,000 infants each year in the United States. Fetal infection can result in a wide range of outcomes for children, from asymptomatic infection to severe disability and death. Birth prevalence reflects all neonatal infections detected at birth as a result of both primary and recurrent infections. Birth prevalence also varies geographically and is estimated to be 0.48-1.3% in the United States, 0.54% in The Netherlands, and 1.08% in Brazil.

The prevalence of prior exposure in women of childbearing age varies by region and income and ranges from 40-83%. Of seronegative women, 1-4% will acquire a primary infection during pregnancy, and the majority of these women will be asymptomatic ( Figure ). Seroconversion varies by socioeconomic status, with 1.6% of women from middle- and high-income groups seroconverting during pregnancy, compared to 3.7% of women in low-income groups. Less commonly, women with a prior CMV infection may experience either reinfection with different strains, or reactivation of disease. While congenital infection can occur with reactivation or recurrent infection, it is far more likely to occur in the setting of maternal primary infection.

Maternal and neonatal risks for cytomegalovirus (CMV) infection.

SMFM. Congenital CMV diagnosis and antenatal management. Am J Obstet Gynecol 2016 .

What is the epidemiology of CMV?

Congenital CMV, a herpesvirus, is the most common viral infection of the fetus and is the leading nongenetic cause of congenital deafness, affecting nearly 40,000 infants each year in the United States. Fetal infection can result in a wide range of outcomes for children, from asymptomatic infection to severe disability and death. Birth prevalence reflects all neonatal infections detected at birth as a result of both primary and recurrent infections. Birth prevalence also varies geographically and is estimated to be 0.48-1.3% in the United States, 0.54% in The Netherlands, and 1.08% in Brazil.

The prevalence of prior exposure in women of childbearing age varies by region and income and ranges from 40-83%. Of seronegative women, 1-4% will acquire a primary infection during pregnancy, and the majority of these women will be asymptomatic ( Figure ). Seroconversion varies by socioeconomic status, with 1.6% of women from middle- and high-income groups seroconverting during pregnancy, compared to 3.7% of women in low-income groups. Less commonly, women with a prior CMV infection may experience either reinfection with different strains, or reactivation of disease. While congenital infection can occur with reactivation or recurrent infection, it is far more likely to occur in the setting of maternal primary infection.

Maternal and neonatal risks for cytomegalovirus (CMV) infection.

SMFM. Congenital CMV diagnosis and antenatal management. Am J Obstet Gynecol 2016 .

What are the fetal risks from primary maternal CMV infection in pregnancy?

A primary CMV infection is the first exposure to the virus and it is concerning when it occurs during pregnancy. The likelihood of congenital infection is highest following primary maternal infection and is reported to be approximately 30-50% ; although some series suggest a rate as high as 70% with third-trimester exposure. Women with primary CMV in pregnancy have a risk of congenital infection of 30-50% and the severity of infection varies widely (Best Practice) . Recent series of pregnancies with primary infection demonstrate increasing frequency of congenital infection with gestational age, from approximately 30% in the first trimester to 40-70% in the third trimester. None of the infants infected during the third trimester in these reports experienced symptomatic disease. There is some variation across gestation, with earlier infection thought to be less frequent but more severe. CMV transmission after preconception primary infection has also been reported. One study found an 8.3% transmission rate when the primary CMV infection occurred 2-18 weeks prior to the last menstrual period. Another study found a similar rate of transmission, 8.8%, after preconception exposure, but importantly, none of those infants showed symptoms at birth. There does not appear to be a seasonal variation to the risk of maternal infections.

Among women with a primary infection, 18% of their infants will be symptomatic at the time of birth. These symptoms include jaundice, petechial rash, hepatosplenomegaly, and death. In a classic article, infants were followed up over time to estimate risks of long-term sequelae. Of those not symptomatic at birth, up to 25% experience sequelae during the first 2 years of life. These sequelae include sensorineural hearing loss, cognitive deficit with an intelligence quotient <70, chorioretinitis, seizures, and death. Among infants followed up to 5 years of age, development of sequelae occurred as late as 72 months. Severe illness appears to be more likely among fetuses whose mothers experience primary infection during the first half of pregnancy.

What are the fetal risks from recurrent maternal CMV infection?

Recurrent CMV infection can occur after prior maternal exposure to CMV and does not preclude neonatal infection. Most of the literature surrounding recurrent CMV infection resulting in a symptomatic neonate comes from case reports. Of women with recurrent CMV infections, <1% of offspring are symptomatic at birth. However, 8% of offspring will develop sequelae including hearing loss, chorioretinitis, or milder neurological sequelae such as microcephaly by age 2 years and 14% by age 5 years. In 1 series, none of the offspring of women with recurrent infection died in the follow-up period.

How is primary maternal CMV infection diagnosed?

Testing for maternal CMV infection generally occurs after suspicious ultrasound findings. The most common ultrasound findings warranting investigation for CMV infection include echogenic fetal bowel, cerebral ventriculomegaly and calcifications, and fetal growth restriction ( Table ). Hepatic calcifications, microcephaly, and subependymal cysts have also been described. One method for diagnosis of primary infection is seroconversion but this requires serial serology, a strategy unlikely to be feasible for all pregnancies in the United States. Traditional teaching is that the presence of IgM antibody indicates acute infection. However, in the case of CMV serology in pregnancy, <10% of women with positive IgM congenitally infect their infants, compared with 30-50% of those with seroconversion. This is largely related to the high (up to 90%) false-positive rate for CMV-IgM assays performed by standard enzyme-linked immunoassays, especially those performed in commercial, nonreference laboratories. IgM can be produced during nonprimary infections, which are associated with a much lower risk of congenital infection, as well as in response to other viral infections, such as Epstein-Barr virus. IgM can also persist for months following primary infection, potentially predating pregnancy by a significant time lag. Therefore, the presence of IgM alone should not be used for diagnosis.

The IgG avidity assay is a tool that can be used to more accurately detect a primary infection than IgM alone. Antibodies produced at the time of a primary infection have lower antigen avidity than do those produced during nonprimary response or later in a primary immune response. Over time, the maturation of the antibody response results in higher antibody avidity. Low to moderate avidity antibodies are encountered for 16-18 weeks following primary infection. Therefore, a low avidity IgG result in combination with a positive IgM antibody is indicative of infection within the preceding 3 months, allowing more accurate diagnosis of primary infection occurrence during or shortly prior to pregnancy. Lazzarotto et al published the results of a cohort of 2477 women referred for positive IgM. They performed immunoblot to confirm positivity of IgM and found 55% were not confirmed by immunoblot, and had high avidity until IgG. Of the 514 women found to have confirmed IgM, as well as low to moderate avidity, 25% delivered a congenitally infected infant, a rate similar to the 30% among those with documented seroconversion.

Despite the availability of avidity testing for primary CMV infection, the diagnosis may remain unclear because the significance of intermediate avidity and the appropriate cut-off for low avidity are not well established. Alternate methods of diagnosis are also available and include maternal serum or urine virology testing, although this does not correlate well with timing of infection or neonatal outcomes. Newer methodologies include using interferon gamma release assays or intracellular cytokine staining, but these tests are mainly used for diagnosis of immunocompromised patients. For women suspected of having primary CMV infection in pregnancy, we recommend that diagnosis should be either by IgG seroconversion or with positive CMV IgM, positive IgG, and low IgG avidity (grade 1B).

How is a diagnosis of fetal CMV infection made?

In the setting of a documented primary maternal infection but without confirmed fetal infection, the risk of severe fetal sequelae is approximately 3% and risk of any adverse outcomes is approximately 8%. Based on serology alone, there is a >90% chance of a good outcome free of sequelae. The sensitivity of prenatal diagnosis techniques varies widely depending on the population selected, the gestational age at the time of the technique, as well as the gestational age at the time of fetal infection. The more common method used to diagnose fetal infection is by amniocentesis. The only other diagnostic option, cordocentesis, provides similar sensitivity and specificity to amniotic fluid CMV testing, but with a higher complication rate than amniocentesis.

Amniocentesis is the best option as a prenatal diagnostic tool to detect fetal congenital CMV infection, performed >21 weeks of gestation and >6 weeks from maternal infection (grade 1C). With the ability to detect CMV-DNA through polymerase chain reaction (PCR) testing, this modality allows for near exclusion of antenatal fetal infection. A negative PCR for CMV by amniocentesis, if performed >21 weeks of gestation or >6-7 weeks from maternal primary infection, has specificity between 97-100%. Importantly, there may be false-negative findings if the amniocentesis is performed 6 weeks from maternal exposure, but <21 weeks of gestation, such that delaying an amniocentesis until 21 weeks of gestation or repeating an early negative amniocentesis is recommended. While the sensitivities vary from 45-80%, the positive predictive value of the test also approaches 100%, though false-positive CMV by PCR has been reported. Data are conflicting, though, on whether the amount of detectable viral load is related to the severity of infection. Fetal blood CMV-DNA assessment via PCR has also been described via cordocentesis. The sensitivity of this method is similar to that of amniotic fluid testing, but the higher complication rate associated with cordocentesis makes amniocentesis the recommended primary method for diagnostic testing. Women should be counseled that the severity of infection cannot be determined by amniocentesis.