Recent MDx advances make congenital CMV testing more feasible

April 24, 2023

Human cytomegalovirus (CMV) could practically be a tale of two pathogens. Among healthy adults, CMV infections are quite common and largely asymptomatic. Indeed, by age 40, at least half of all people in the United States will have had a CMV infection; most will never even know it happened.1 But in developing babies or newborns, CMV is no harmless visitor. Congenital CMV has been associated with pregnancy loss, and babies born with congenital CMV are at significantly increased risk of hearing loss and neurodevelopmental issues.

With early antiviral treatment, these babies have much better outcomes. Unfortunately, current CMV testing models do not typically enable such quick intervention. To distinguish between congenital CMV — cases passed from mother to fetus through the placenta — and the less dangerous CMV infections that occur after birth, testing must be performed in the first few weeks of life. But CMV is rarely included in newborn screening tests, and symptoms of congenital CMV can be so difficult to spot that diagnostic testing is seldom ordered in this short window.

Recent advances in rapid molecular testing have made it easier to perform CMV testing in newborns, generating results quickly enough to allow for intervention as soon as possible. In addition, efforts to raise awareness about the importance of congenital CMV testing have begun to pay off with the consideration of new universal screening policies.

The health risk 

Like Zika and other viruses that can wreak havoc in a developing fetus, congenital CMV can lead to severe symptoms that manifest in the months and years after birth. The vast majority of babies born with CMV — about 90% — have no signs of infection and appear completely healthy. But this is deceiving: babies born with CMV are at risk of developing symptoms later and can even die from complications of the infection.

Common (and typically lifelong) symptoms for babies who survive the infection include hearing loss, developmental delays, and neurodevelopmental abnormalities such as seizures or microcephaly. Indeed, congenital CMV is the most common nongenetic cause of hearing loss in infants. In the United States, about 1 in every 200 babies born each year — a total of 30,000 babies — is believed to have congenital CMV. Just 1% of those babies are diagnosed with CMV based on clinical signs and symptoms.

There is hope for these babies, but only with early intervention. Antiviral treatments such as ganciclovir or valganciclovir may mitigate some symptoms and give healthier outcomes to these infants.2,3 But these treatments are most effective when administered in the first months of life. That, of course, is only possible when congenital CMV cases are caught early enough to allow it.

Universal screening

CMV infections must be detected in the first three weeks of life to diagnose possible congenital CMV infection. In some states, CMV testing is recommended for infants who fail their newborn hearing screening. While this makes sense on paper, it does not hold up in real-world practice. Newborn hearing screening can be unreliable, with a sizable number of false positives and false negatives. Even when accurate, the screen does not detect cases of CMV-infected babies whose hearing loss may not be present at birth and instead occurs later in life due to the infection. The recommendation for CMV testing based on hearing screening results often occurs after mothers and babies have been released from the hospital, letting too many of these families slip through the cracks due to a lack of follow-up. A special consideration is premature babies who may be hospitalized for many weeks after birth but may not receive a newborn hearing screen until they are well past the 21-day window in which CMV testing could differentiate a congenitally acquired infection.

A far more effective approach would be to include CMV testing as part of each state’s universal newborn screening programs. By testing all babies shortly after birth, the clinical laboratory community would have a chance to identify and confirm every case of congenital CMV and guide physicians to the appropriate treatment in a clinically relevant time frame. In addition, universal screening would finally permit a more comprehensive view of the incidence of congenital CMV — numbers that have until now been based on estimates and inference.

Recently, there has been some progress on this front. Minnesota just became the first state to implement universal CMV screening for all newborns, adding it to the more than 60 other conditions for which the state recommends testing at birth. In 2019, the National CMV Foundation nominated CMV for inclusion in the Recommended Uniform Screening Panel, the list of conditions and disorders recommended by the Department of Health and Human Services for newborn screening in all states.

Universal CMV screening is beginning to gain traction outside the United States too. A recent study from researchers in Italy evaluated the benefit of universal screening for congenital CMV infections by testing all newborns at three clinical sites. The study, which covered more than 3,000 babies, identified 21 CMV infections.4 Recognizable clinical symptoms of congenital CMV were only noted in three cases. The authors pointed out that without universal screening, the rest of the infected babies would likely not have been diagnosed until long past the ideal time frame for early intervention.

Molecular testing

Because of the pressure to diagnose congenital CMV cases as quickly as possible, traditional tests such as viral cultures have never been a good fit for this clinical need. Any assay that takes weeks to return results or lacks sensitivity is incompatible with the stringent requirements for newborn CMV testing.

Molecular diagnostic tests offer a more promising approach, but not every specimen type has delivered the sensitivity required for a screening test. Although dried blood spots (DBS) would be an ideal sample type since blood is already collected on Guthrie cards from every newborn in the U.S., study results have shown that DBS-based tests can lack sensitivity.5 Importantly, a positive DBS PCR confirms congenital CMV but a negative result does not rule it out.6 However, robust and sensitive PCR-based assays can be run on either saliva swabs or urine samples, making them flexible enough for newborns and compatible with the sample types recommended by the Centers for Disease Control and Prevention and many expert-developed guidelines for congenital CMV diagnosis. In addition, molecular tests typically produce reliable results more quickly than their conventional counterparts, delivering answers in a matter of hours and enabling recommended confirmatory urine testing following a positive saliva swab test.

Not all molecular tests are equally easy to deploy, though. For clinical laboratory teams looking to implement congenital CMV testing for the first time, the most straightforward approach might come from a commercial sample-to-answer system. Such systems are highly automated, running all steps — from sample preparation and processing to data generation — without user intervention. Technicians load the sample and reagents into a cartridge or consumable device, place it in the instrument, and press a button to start the run. 

There are several sample-to-answer systems on the market, and they typically share a number of critical features. They minimize the need for extensive staff training because they are designed to be very user-friendly. They usually take up little bench space and are built in compact footprints for notoriously space-limited laboratories. They produce results quickly, potentially in just an hour or two, and support a broad menu of tests because most platforms can be used with a variety of test-specific cartridges or consumables. Sample-to-answer systems are usually sold by commercial diagnostic developers, and their test consumables are often cleared by the U.S. Food & Drug Administration for use as in vitro diagnostics.7 With all of these traits, easy-to-install automated systems can be an effective option for congenital CMV testing at hospitals where babies are born.

Universal screening will be more technically feasible as more testing options become available for easy, rapid, and cost-effective congenital CMV diagnosis. With new studies demonstrating its benefit across populations, policymakers may follow suit. Clinical lab teams may find it useful to start planning now for increased demand for congenital CMV testing.


1. Jean Beltran PM, Cristea IM. The life cycle and pathogenesis of human cytomegalovirus infection: lessons from proteomics. Expert Rev Proteomics. 2014;11(6):697-711. doi:10.1586/14789450.2014.971116.

2. Centers for Disease Control and Prevention. (2020). Babies born with congenital cytomegalovirus (CMV). Retrieved March 27, 2023, from

3. Ross SA, Kimberlin D. Clinical outcome and the role of antivirals in congenital cytomegalovirus infection. Antiviral Res. 2021 Jul;191:105083. doi: 10.1016/j.antiviral.2021.105083.

4. Chiereghin A, Pavia C, Turello G, Borgatti EC, et al. Universal Newborn Screening for Congenital Cytomegalovirus Infection - From Infant to Maternal Infection: A Prospective Multicenter Study. Front Pediatr. 2022 Jul 6;10:909646. doi: 10.3389/fped.2022.909646. PMID: 35874574; PMCID: PMC9298552.

5. Dollard SC, Dreon M, Hernandez-Alvarado N, et al. Sensitivity of dried blood spot testing for detection of congenital Cytomegalovirus infection. JAMA Pediatr. 2021;175(3):e205441. doi:10.1001/jamapediatrics.2020.5441.

6. Boppana SB. Dried blood spot real-time polymerase chain reaction assays to screen newborns for congenital Cytomegalovirus infection. JAMA. 2010;303(14):1375. doi:10.1001/jama.2010.423.

7. Fernholz EC, Vidal-Folch N, Hasadsri L. Rapid and direct detection of congenital Cytomegalovirus using a commercial real-time PCR assay. J Clin Microbiol. 2023;61(3):e0178122. doi:10.1128/jcm.01781-22.