By the Society for Maternal-Fetal Medicine (SMFM); Brenna L Hughes, MD, MSC; and Cynthia Gyamfi-Bannerman, MD, MSC
Created in partnership with the Society for Maternal-Fetal Medicine. SMFM was established in 1977 to "give MFM physicians and scientists a place to share knoweldge, research and clinical best practices in order to improve care for moms and babies."
This Maternal-Fetal Medicine (MFM) consult provides information regarding the diagnosis and antenatal management of congenital cytomegalovirus (CMV), the most common perinatal viral infection leading to neonatal and childhood sequelae, which affects nearly 40,000 infants each year in the United States. The purpose of this document is to review diagnosis of primary maternal and fetal CMV infection, and assess whether antenatal therapy is warranted.
Q. What is the epidemiology of CMV?
A. CMV, a herpes virus, is the most common viral infection of the fetus and 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.
The prevalence of prior exposure in women of childbearing age varies by region and income and ranges from 40% to 83%. Of the 1% to 4% of seronegative women who acquire a primary infection during pregnancy, the majority will be asymptomatic. 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 re-infection with different strains or reactivation of disease. Although congenital infection can occur with reactivation or recurrent infection, it is far more likely in the setting of maternal primary infection.
Q. What are the fetal risks from primary maternal CMV infection in pregnancy?
A. 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 reportedly approximately 30% to 50%, although some series suggest a rate as high as 70% with third-trimester exposure. 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% to 70% in the third trimester. None of the infants infected during the third trimester in these reports experienced symptomatic disease. Some variation is seen 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 to 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. Risk of maternal infection does not appear to have seasonal variation.
At birth, 18% of infants born to women with primary infections will have symptoms, which include jaundice, petechial rash, hepatosplenomegaly, and death. In a classic paper, infants were followed over time to estimate risks of long-term sequelae. As many as 25% of infants who are asymptomatic at birth will experience sequelae during the first 2 years of their lives. These problems include sensorineural hearing loss, cognitive deficit with an IQ <70, chorioretinitis, seizures, and death. Among infants followed to age 5 years, 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.
Q. What are the fetal risks from recurrent maternal CMV infection?
A. CMV infection can reoccur 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. Fewer than 1% of offspring of women with recurrent CMV infections 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 and 14% by age 5. In one series, none of the offspring of women with recurrent infection died in the follow-up period.
Q. How is primary maternal CMV infection diagnosed?
A. Testing for maternal CMV infection generally occurs after suspicious ultrasound findings. The most common such findings warranting investigation for CMV infection include echogenic fetal bowel, cerebral ventriculomegaly and calcifications, and fetal growth restriction. Hepatic calcifications, microcephaly, and subependymal cysts have also been described. One method for diagnosing primary infection is seroconversion but it requires serial serology, a strategy unlikely to be feasible for all pregnancies in the United States. Traditional teaching is that the presence of immunoglobulin M (IgM) antibody indicates acute infection. However, in the case of CMV serology in pregnancy, fewer than 10% of women with positive IgM congenitally infect their infants, compared with 30% to 50% of those with seroconversion. The presence of IgM alone should not be used for diagnosis.
The immunoglobulin G (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 non-primary response or later in a primary immune response. Over time, maturation of the antibody response results in higher antibody avidity. Low to moderate avidity antibodies are encountered for 16 to 18 weeks following primary infection. Therefore, a low-avidity IgG result combined with a positive IgM antibody is indicative of infection during the preceding 3 months, and thus facilitates more accurate diagnosis of primary infection that occurs during or shortly prior to pregnancy.
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 available 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 (IGRAs) or intracellular cytokine staining, but these tests are mainly used for diagnosis in immunocompromised patients.
Q. How is fetal CMV infection diagnosed?
A. 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 greater than 90% chance of a good outcome free of sequelae. The sensitivity of prenatal diagnostic techniques varies widely depending on the population selected, the gestational age at the time the technique is used, and the gestational age at the time of fetal infection. Amniocentesis is the more common method used to diagnose fetal infection. The only other diagnostic option, cordocentesis, has sensitivity and specificity similar 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 after 21 weeks’ and more than 6 weeks after maternal infection. Because polymerase chain reaction (PCR) testing can detect CMV DNA, that modality allows for near exclusion of antenatal fetal infection. A negative PCR for CMV by amniocentesis, if performed after 21 weeks’ gestation or 6-7 weeks after maternal primary infection, has specificity between 97% to 100%. Importantly, false negatives are possible if amniocentesis is performed 6 weeks after maternal exposure, but less than 21 weeks’ gestation. Therefore, delaying amniocentesis until 21 weeks’ gestation or repeating an early negative amniocentesis is recommended. Fetal blood CMV-DNA assessment via PCR has also been described via cordocentesis. This method’s sensitivity 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.
Q. What is the role of imaging in assessing fetal infection?
A. Ultrasound imaging cannot diagnose a fetal infection. Further, ultrasound imaging suggests fetal infection in fewer than 50% of infected fetuses, so when used alone, it is not appropriate as a diagnostic test for congenital CMV infection. The most common ultrasound findings in congenitally infected fetuses are cerebral calcifications, microcephaly, and echogenic bowel. Magnetic resonance imaging (MRI) has been used to examine fetuses suspected of being infected, but its use is controversial. Normal brain imaging does not necessarily predict normal neurodevelopmental outcome, particularly since hearing loss is frequently progressive in congenital CMV. At this time, the data regarding the addition of MRI to ultrasound evaluation are insufficient to recommend routine use in evaluation for congenital CMV infection.
Q. Is universal screening for CMV infection recommended?
A. Routine screening for CMV infection during pregnancy, whether universal or targeted, is not recommended. Routine CMV screening does not meet several of the criteria for an effective screening test at this time and, therefore, is not recommended outside of a research setting. Currently, the only available intervention studied in a randomized trial showed no benefit over placebo. Moreover, routine screening can lead to unnecessary intervention, which could, in fact, be harmful. The interventions that are available each have adverse effects (some for the mother, others for the fetus), are intensive to administer, and are without clear evidence of benefit.