A condition which affects at least 20 000 babies born in the US each year and leaves about 4 000 of them with serious long-term health impacts, including deafness, has been surprisingly under-researched, with little known about the disease.
Now some health experts are urging more robust screening for cytomegalovirus, or CMV, in newborns.
In the 1980s, after US paediatrician Mark Schleiss’ months-old infant patient died of pneumonia in the ICU, the autopsy found the baby had disseminated cytomegalovirus, which had caused his pneumonia and then his death.
Schleiss said the diagnosis of CMV drew his interest.
“I was struck by… how little anybody knew about CMV,” Schleiss, now a physician-scientist at the University of Minnesota, told STAT News.
Even if doctors had caught the condition, there was little they could have done: Antivirals were relatively new then, and the first drug for CMV would not be approved for another year. In the decades since, there has been little progress in treating CMV, which appears in 20 000 babies born each year in the US and leaves some 4 000 infants annually with devastating long-term health problems.
There is no vaccine against the virus, and the best-studied and most-used treatments are the antiviral approved three decades ago and another structurally similar drug.
Experts say there is little public awareness about CMV compared with other viral infections that can infect a foetus in utero, such as HIV, Zika and toxoplasmosis, all of which are far rarer than CMV infections.
Professional societies recommend pre-pregnancy counselling and monitoring for HIV, but not for CMV. And testing for the infection in newborns isn’t widespread.
“It’s clear that this field is really lacking in progress,” said Laura Gibson, an infectious diseases physician at UMass Memorial Health. “It’s been frustrating to all of us over decades.”
That is starting to change, as state public health committees and legislatures begin to debate whether to mandate doing more robust screening for CMV. In 2019, Ontario became the first region in the world to test every baby for CMV. This year, Minnesota followed suit.
CMV is short for cytomegalovirus, which describes both a group of viruses (one of which infects humans) and the disease it causes. Like flu, it’s common and often harmless, shrugged off as a non-problem. But like HIV, CMV is resilient and tough to clear out: CMV cycles between periods of dormancy and activity. Once someone is infected, they carry the virus throughout their lifetime.
“It’s a constant interaction between the virus and the immune system, as opposed to the flu that comes and goes,” said Gibson. “It lives with us for life.”
A CMV infection is particularly devastating for a foetus, because the virus has a proclivity for infecting neural stem cells. One study found CMV increased the risk of stillbirth by more than eight times. In babies who survive, the virus can cause neurodevelopmental delays and disabilities, including cerebral palsy, seizures, vision impairment and progressive hearing loss.
Hearing loss is by far the best studied consequence of congenital CMV – CMV is the foremost non-genetic cause. But it’s not always apparent: 15% of infected babies will appear healthy at birth, only to lose their hearing later in life.
“Congenital CMV is often a progressive disease,” Gibson said. “Whatever we find on testing at birth, any of those parameters can get worse over time, over years.”
Yet CMV receives relatively little attention compared with other prenatal infections that also have significant health impacts, but are much rarer, such as Zika. Even doctors specialising in caring for children said they were taught little about CMV in their training.
Megan Pesch, a developmental and behavioural paediatrician at the University of Michigan who completed her medical degree two decades later, said the only time CMV was mentioned in her training was as the letter C in the mnemonic device TORCH, used to help students remember a set of congenital infections.
Pesch now has an intimate understanding of CMV’s toll – but not from her medical training. In 2018, after completing residency and fellowship training in paediatrics, she gave birth to her third child, a daughter named Odessa.
Pesch, who is also president of the National CMV Foundation, said a day later, the first sign that something might be wrong emerged. Odessa did not react to the sounds in her first newborn hearing screen. “Many babies fail this hearing screen. Nine out of 10 times it’s just a false positive,” said Pesch. “So I didn’t worry.”
But six weeks later, Odessa didn’t pass a repeat screen. Further testing revealed she was completely deaf.
At first, it was suspected the cause was genetic.
Pesch asked to test Odessa’s urine for CMV when she was three-months-old. It came back positive, which could have signalled either congenital CMV or an infection after birth. A head ultrasound revealed abnormalities consistent with congenital CMV.
Odessa, who was four-months-old, started an off-label course of twice-daily antivirals for the next six months. A blood sample taken from when she was days old later tested positive for congenital CMV.
Odessa, now four, needs braces to support her legs. She tried cochlear implants, but they didn’t work well. She also has autism, which is common in congenital CMV patients.
Physicians can only intervene in the days and weeks after birth, not before. There are no tests that conclusively determine active CMV infection of a mother during pregnancy. And in the small subset of cases where a parent’s test shows a new CMV infection, there are no proven medicines to treat a foetus in utero.
Professional societies don’t recommend CMV screening for these reasons. As a result, said Pesch, parents rarely learn about it. “ACOG actually recommends that people do not counsel their patients about CMV prevention because to implement it would be burdensome and impractical for women,” she said, referring to the American College of Obstetricians and Gynaecologists. “I’m baffled why people don’t take it more seriously.”
Where the scientific and medical communities have arguably made some progress is in newborn screening tests. Nearly every baby born in the US gets a heel prick in the hospital to test for rare, often hidden health conditions that are fatal or life-altering unless promptly treated, and all babies also undergo hearing tests. Historically, these tests haven’t looked for CMV at birth.
In 2013, Utah became the first state to start some sort of screening for congenital CMV. The legislature passed a Bill that requires public education of CMV and, when a newborn has failed their hearing test, the option to test for CMV.
Unlike conventional newborn screening, performed by state health departments, Utah providers test urine, which contains more DNA from the CMV virus. Hospitals test the samples and report the results to the health department, which tracks follow-up care.
Today, 14 states perform follow-up testing for CMV when a baby doesn’t pass a hearing test. But the approach is limited in its ability to catch CMV, due to its progressive nature. An influential study found that around half of congenital CMV patients who later develop hearing loss are missed because they pass hearing screening early on.
Universal CMV screening has “been debated in many states for years”, said Schleiss. Even a decade ago, Utah’s law was controversial.
States can mandate specific newborn screening tests be performed without the explicit consent of parents – meaning state health departments are very particular about deciding which conditions to screen for.
“The idea is the state is taking rights away from parents. They’re saying: ‘This condition is important enough for us to screen that you don’t get a say in whether or not your baby is screened for this mandated condition,’” said Anne Comeau, deputy director of the New England Newborn Screening Programme and a professor at UMass Chan Medical School.
“Typically, you need a screening test for a disease that has a bad outcome, if it isn’t detected, for which an intervention is available,” said Schleiss. Among experts, CMV is controversial from that perspective. It causes clear issues – chief among them, progressive hearing loss – in 15% of cases.
But in the other 85%, any potential health effects are less apparent. (A continuing concern is that the non-hearing effects of congenital CMV are understudied because most CMV cases aren’t identified; in a small study of 34 clinically asymptomatic infants with congenital CMV, 56% had some form of abnormality identified upon further study.)
Schleiss has continued to push for greater awareness of CMV over the decades. Along with affected families, he started lobbying Minnesota legislators in 2015 on the issue. One proposal for CMV education made it into a spending Bill and to the governor’s desk, where it got vetoed in 2018.
Additionally, Schleiss started working with the Minnesota Department of Health and the US Centres for Disease Control and Prevention (CDC) to test blood and urine samples of newborns for CMV. The results of that study, published in February 2021, showed that blood from heel pricks could achieve a sensitivity of around 75%, due in large part to advances in DNA extraction technologies.
This was akin to a proof of concept that made blood tests, easily integrable into existing newborn screening panels, feasible. “Do we need a better test? Yeah, we do,” said Schleiss. But, he added, “don’t let the perfect be the enemy of the good”.
In 2021, Schleiss campaigned for another Bill that would require an outreach programme for congenital CMV education among prospective parents and health care providers.
That Bill was named the Vivian Act – for a now-nine-year-old Minnesotan with congenital CMV – and would also require Minnesota’s newborn screening advisory committee to consider adding CMV to the state’s screening panel.
The Bill passed, and the question came before the screening committee. The panel of experts examined how accurate the tests were, whether insurance companies would balk at the cost of testing, and whether health systems and labs would need more trained staff.
Last year, they agreed it was worthwhile and last month, Minnesota became the first state to screen all newborns for congenital CMV.
Some physicians still aren’t convinced universal screening is the right move. Carlos Oliveira, a paediatric infectious diseases physician at Yale and director of its congenital infectious diseases programme, has evaluated many children for CMV since a Connecticut law mandating targeted CMV screening came into effect in 2016.
His patients receive urine draws, blood samples, eye exams, ultrasound imaging, and sometimes MRI scans. He said parents often feel a sense of guilt with the diagnosis, because the virus is passed from mother to child, and anxiety over the potential health impacts.
But more often than not, he said, the stress parents are put through doesn’t turn out to be warranted. “The problem with CMV is that the majority of babies who are infected before birth don’t have any problems,” Oliveira said. “I don’t really care if the baby has CMV if nine out of 10 of them will have absolutely no long-term ramifications.”
“That’s my problem with universal screening,” he summed up. “It’s a huge policy affecting a lot of people and I have a hard time justifying the good for that.”
It’s an increasingly common issue in screening for disease, as advances in science allow for detecting more disorders: how to best balance the needs of some patients against the risks of false alarms or unnecessary treatment. The field will need to grapple with that and other questions, such as how accurate a screening test needs to be to prove worthwhile, as it looks to finally move forward on CMV.
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