We discuss the prevalence, manifestations, and treatment of congenital CMV infection. We are joined by Elizabeth “Kaili” Stehel, MD, Associate Professor of Neonatal-Perinatal Medicine at the University of Texas Southwestern Medical Center.
Dr. Neeta Goli:
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern newborn nursery.
Dr. Neeta Goli:
Welcome back to the podcast. In today's episode, we'll be discussing congenital cytomegalovirus, or CMV. We're recording remotely due to the ongoing COVID pandemic. We are joined today by Dr. Kaili Stehel, who works in the newborn nursery at Parkland Hospital and is an associate professor of pediatrics at UT Southwestern in the division of neonatal-perinatal medicine.
Dr. Kaili Stehel:
Hello?
Dr. Neeta Goli:
Hi, Dr. Stehel. Thanks for joining us today.
Dr. Kaili Stehel:
Thank you so much for having me.
Dr. Neeta Goli:
So to get started, cytomegalovirus is a member of the herpesviridae family of viruses. It is ubiquitous in humans, with an estimated 60% of the U.S. population having been exposed at some point. In healthy individuals, it might be asymptomatic, or it can cause upper respiratory systems or flu-like illness. If a pregnant woman contracts CMV, however, there is a chance that her infant might be infected. So can you first just talk about CMV infection in general?
Dr. Kaili Stehel:
Yes. Okay. So I'm really looking forward to talking to you today about my favorite congenital infection, and you're probably scratching your head and wondering why.
Dr. Kaili Stehel:
So I feel like CMV and its impact is really underappreciated. So I'm going to take a minute before I start about CMV and just talk about rubella. And I want to do that because it was before most of us were practicing, and I believe we can get congenital CMV to where we are with congenital rubella syndrome right now. So the last major rubella epidemic in the United States was in 1965. And infection in pregnant women caused 10,000 miscarriages, 2,000 newborn deaths, 20,000 babies to be born with congenital rubella syndrome. And remember that the classic triad for that was cataracts, cardiac problems, and deafness.
Dr. Kaili Stehel:
So immunization against rubella began in 1969, and now, if you fast forward to today, congenital rubella is essentially eliminated. So from 10 years, from 2005 to 2015, there were only eight babies reported in the U.S. It's basically case reports reported every couple of years. Mainly, they're imported or associated with travel, but they don't have to be. And if you do the math, that is less than one in four million live births because it's less than one per year. And that's a success story, and I think we can get there with CMV. But to do that, we have to talk about it like we are today.
Dr. Kaili Stehel:
So, where are we now? We don't have any systematic recommendations for testing for pregnant ladies. We don't have systematic recommendations for universal testing for infants. There's no required reporting. There's no currently approved vaccine. And I don't want to focus on all the negatives today. We've made a lot of headway. In 2004, the National Vaccine Advisory Committee classified work on CMV vaccine as a top priority, that was based on the story that I just told you about rubella. The disease burden of congenital CMV today is as high as the disease burden was from congenital rubella.
Dr. Kaili Stehel:
We have made some progress. Vaccine work is underway. We have a treatment for fetuses that shows promise that's still not recommended universally, but it is available, and many high-risk newborns are screened. We have treatments for infants that have serious symptoms, either during the pregnancy or after birth. And so today, I really hope to convince you that CMV is worth your attention. In particular, vaccines before people become pregnant and universal screening of newborns are goals that I hope to see achieved in my career.
Dr. Kaili Stehel:
Okay, so now to answer your question. So you want me to address CMV in general. So CMV is acquired from contact with infected bodily fluids like saliva, urine, genital secretions, breast milk, but also blood, and organs. And this person that has the infected bodily fluid could be symptomatic or asymptomatic. So your first infection is called the primary infection. And after that primary infection, CMV persists in your body, in your cells, in your tissues, and it becomes latent, and you could have another infection. Those are called non-primary infections. They're either re-infection with a different strain, or you can re-activate your same strain.
Dr. Kaili Stehel:
So congenital CMV infection comes from intrauterine transmission from the mom to the baby, across the placenta. And there's also perinatal transmission, and that's from exposure to infected secretions at birth or from breastfeeding, and those have different outcomes. So most infections of CMV, both primary and non-primary, so that would be your first infection, or non-primary, either re-activation or re-infection with another strain. They're asymptomatic, especially in immunocompetent hosts.
Dr. Kaili Stehel:
So we've also seen in school, and we tend to think of the life-threatening complications in patients with a compromised immune system, maybe in the setting of AIDS or a transplant recipient. But the highest disease burden from CMV is actually from congenital infection, and that's why I'm talking about it with you today. So it's just like congenital rubella, that picture. We're going to go over the numbers.
Dr. Kaili Stehel:
So lots of people are working on this, and one of them is Michael Cannon, from the National Center of Birth Defects and Developmental Disabilities at the CDC. And he looked around the world at studies of CMV seroprevalence. So you already mentioned that 50 to 60% of the population in the United States has been exposed, and that holds true for women of child-bearing age. And even closer to home in Texas, 40% of women of child-bearing age have been exposed to CMV.
Dr. Kaili Stehel:
As you could imagine, seroprevalence increases with age. And that makes sense because it's due to our cumulative past exposure, and there are some things that put you at risk. So if you're non-white, you are 20 to 30% higher seroprevalence. If you are a low socioeconomic group, you're higher. Women tend to be higher than men in most studies. And these seem to be related to our child-bearing practices, like child-rearing practices, breastfeeding, and sexual practices. But the variations in seroprevalence can't be explained just by poverty, and youth, and crowding because some places that are developed that don't have extreme poverty and have high education, they have high seroprevalence, and Japan would be one example.
Dr. Kaili Stehel:
So I kind of want to turn these numbers backwards, so the important issue, you told me that 60% have been exposed. Well, that means that a substantial percentage, a huge amount, just in the United States alone, half the women of reproductive age are CMV seronegative, and that's not good. This translates into being at high-risk for primary CMV infection during pregnancy, which is a time of relative immunocompromise, and, therefore, at higher risk of giving birth to a baby who will suffer from a CMV-related disability.
Dr. Kaili Stehel:
So if you're not immune when you're pregnant, you can acquire primary infection during pregnancy. And babies born to mothers with primary infection are at much greater risk of having long-term disabilities.
Dr. Neeta Goli:
Okay. So that was a really great introduction and background, so I really appreciate that context. So that was prevalence of CMV in general. What about congenital CMV? How common is that these days?
Dr. Kaili Stehel:
Okay. In babies, in the United States, we don't have universal newborn screening. And, remember, it's not a reportable illness, unlike HIV or syphilis, so our best estimates are coming from centers in the United States that are actively researching this. And that would be places like Houston, Birmingham, Salt Lake City, there's a number of them. And then, for special populations, like at Parkland, we have 85% Hispanic population delivering. And so for those numbers, we would have to look around the world, like in Mexico.
Dr. Kaili Stehel:
So our best estimate is that CMV occurs in 1 in 100 to 1 in 200 live births. So that would be higher in African Americans, lower in Hispanics, and it could be as low as a half... well, 1 in 100 to 1 in 200 going to suffice for our conversation today. So I want to pause, and I'm going to repeat myself.
Dr. Kaili Stehel:
So 1 in 100 to 1 in 200 means that CMV is more common than all the TORCH infections added together. Okay. So bear with me. I'm going to do a little math. And I'm going to overestimate the TORCH infections just to make my point. I'm going to go on the high end of that range. And I'm going to go on the low end of CMV infection, okay?
Dr. Kaili Stehel:
So let's say that CMV is 1 in 200, so that makes 500 per 100,000. We're going to do it like this because we want to talk about Toxo, which is 1 in 10,000, that makes 10 per 100,000. We're going to add these all up. Rubella, we already said, was case reports. HIV is between 0.2 to 5 per 100,000, highest here, but that'd be 10 times higher than if you're White, and so that's going to be 5 per 100,000. Herpes would be 1 in 2,000 to 1 in 3,000. That's 30 per 100,000. Syphilis, which is on the rise, is 11 per 100,000. And even, let's just include group B strep, so that would be all the TORCH infections plus group B strep, so that's about 0.25 per 1000 live births, that's going to be 25 per 100,000.
Dr. Kaili Stehel:
So if you add all those up, Toxo 10, HIV 5, Herpes 30, Syphilis 11, group B strep 25, all per 100,000, that gives 75 per 100,000. And we said that CMV, even going on the low end, is 500 per 100,000, so that's much higher, right? So that's why I say that it's important that we all think about and know about CMV so that we can impact this and make a difference like we have with rubella.
Dr. Kaili Stehel:
So the worst part of this story and all these numbers is that women are not aware of CMV despite this very heavy burden that we just talked about. And so similar to the way that pediatricians don't always discuss breastfeeding, not all OBs discuss CMV with mothers. And I think that's because we don't have a vaccine. We don't have a national recommendation for screening. The treatment is still considered experimental, not recommended in all cases. And it feels like there's not much we can do about it, but that's not the case. There are things that have been proven to work to decrease the burden of congenital CMV.
Dr. Neeta Goli:
If OBs were to discuss it with Mom, what kind of things could they recommend to reduce the risk?
Dr. Kaili Stehel:
Okay, so on the CDC's website's a great handout, and it all has to do with reducing contact and exposure to secretions. So hand washing, particularly after your diaper, feed, bathe. If you wipe someone's snotty nose, if you handle a baby toy, which would have been mouthed, that we should not share cups, plates, utensils, toothbrushes. Don't drink after your child, don't clean up their plate and take the few bites of the chicken nugget that's sitting there. Don't kiss them on or near the mouth. Don't share towels and washcloths. And then, to clean the toys, countertops, and other surfaces that would come into contact with you and your saliva until the child is about six years old.
Dr. Kaili Stehel:
And these sound like it would be very difficult if you have a child. So you say, "Great, I can do that for my first baby, I'm not around another child that's in my home," and you feel like implementing these might make your child feel like you're not being warm and loving, but I think that there are ways to tackle this where the child wouldn't even know. So you kiss them on the top of the head, or on the ear, or in their neck, and not right on the lips.
Dr. Kaili Stehel:
And the other things are going to be kind of invisible. So maybe they ask for a drink of your milk, or lemonade, or whatever you're having, and you hand them their cup, and you just don't drink it anymore, so they don't really notice. A couple of things have shown us that these work. One is that in daycare centers, daycare workers have a much higher CMV seroprevalence than healthcare workers do despite both being exposed. And that's because, in healthcare, we can wear gloves, we are in a setting where we can wash our hands frequently, and we are not in contact with young children's secretions.
Dr. Kaili Stehel:
And the other thing that tells us that this works is that when a mother who is contemplating pregnancy is checked and known to be negative, and she has a child that's known to be positive, and she implements these strategies, she can markedly reduce her conversion rate.
Dr. Neeta Goli:
Hm. Okay. So that's good for us to know for counseling, but, again, it would be the OBs who would be, hopefully, responsible for counseling those moms. Question for you, you mentioned this earlier, so we know that for some pathogens like herpes, there's a significant difference in risk to the fetus, whether the maternal infection is primary or non-primary, or recurrent. Does this also hold true for CMV?
Dr. Kaili Stehel:
Okay. Yes, it does. Okay. So we're going to talk, just a minute, about the red flags in the pregnant woman. So remember that most primary infections in all women, but in pregnant women also, are asymptomatic. They're going to go undetected. We're not going to be able to detect them. Now, sometimes, they'll have flu-like symptoms like fever, fatigue, headache, and if it's not caused by another identifiable infection, those women should be offered serologic testing.
Dr. Kaili Stehel:
Risk factors for primary infection are young moms, meaning less than 15, being non-white, low socioeconomic status, childcare workers have 11% seroconversion rate in the first year, so quite high, people who have young children in the home, and, again, notice how healthcare workers aren't on this list, and that because we're able to pay careful attention to our infection prevention.
Dr. Kaili Stehel:
So during pregnancy, Mom's immune status is really important, as is the timing of her infection. So those two things determine the rate of transmission and the chances that the baby is going to have sequela. Okay, so the highest rate of transmission from the mother to the baby occurs when the mother has a primary infection. So just like all the other numbers, I told you there's a range, so I'm just going to settle on what most people agree. So whether it's just slightly a bit higher or lower, it's still a significant burden.
Dr. Kaili Stehel:
So in this setting, when Mom has a primary infection, there's about 30 to 40% chance of vertical transmission versus 1 to 2% with non-primary infection. So to make matters even worse, the infant born after that primary infection is much more likely to have severe long-term sequela, to be symptomatic. So women who are seropositive before birth are 70% less likely to give birth to an infant with CMV infection. And yet, and this part gets confusing, three-quarters of all infants with congenital CMV infection are born to mothers with non-primary infection, and that's because they can be asymptomatic. They could still have CMV but be asymptomatic, and that is true around the world.
Dr. Kaili Stehel:
So the numbers that I told you, that CMVs 1 in 100 to 1 in 200 live births, that's around the world, whether you live in a country with 100% seroprevalence in women of child-bearing age, or whether you live in a country where it's much lower, say 50%. Okay, so now let's talk about the timing during pregnancy when you have the infection. So if you compare women who are infected in the latter half of pregnancy with the women who develop primary CMV in the first trimester, so CMV in the first trimester, you're much more likely to deliver a baby who has sensorineural hearing loss, up to 40%, versus two or so percent for in the latter half, in other CNS sequela, bad things, mental retardation, cerebral palsy, seizures. So 30% versus much lower, perhaps 10 or 15%.
Dr. Kaili Stehel:
What we just talked about, the timing of infection and the pre-pregnancy immune status, this makes vaccine development very problematic because it means that having had an infection isn't protective against re-activating your own or having another infection. And we already talked about how CMV infection around the world is 1 in 100 live births on average, so that's why we're going to have to find other ways in addition to the vaccine.
Dr. Kaili Stehel:
So for a baby, you can find this fetal infection on sono. And these abnormalities include echogenic bowel, growth retardation, microcephaly, ventriculomegaly, periventricular calcifications in the brain. The placenta can be thickened, the baby can have hydrops, and the amniotic fluid volume can be abnormal. Unfortunately, none of these is specific for CMV, and so there could be other causes. Also, only 15% of CMV-infected fetuses will have these ultrasound abnormalities. But if you do have the abnormalities, and you have a mother with a confirmed primary infection, then it's strongly suggestive of infection.
Dr. Neeta Goli:
So if we do have an infant who has congenital CMV, what are some signs we might see?
Dr. Kaili Stehel:
Okay, so some people like to group them into signs and symptoms that are temporary and those that are that permanent. So if you think about it, the virus is infecting the baby and the bone marrow, and liver, so then the baby's going to have anemia, and that's going to cause, like we talked about, the hydrops, but also the red blood cell production is going to try to move to other sites. The baby's trying to compensate.
Dr. Kaili Stehel:
So that's going to lead to extramedullary hematopoiesis, which is where the baby is making red blood cells out of the bone marrow, so that can lead to the blueberry muffin rash, where they have little sites of red blood cell production in the skin. So it looks like the light color of the muffin with the darker color, the blueberries, like a little spongey mass there. And the liver could be big. The spleen could be big. Baby can have jaundice, particularly with direct hyperbilirubinemia. They can have thrombocytopenia, and that's going to lead to tiny little bruises, so petechiae or bigger ones, purpura, that don't blanch from that thrombocytopenia. They can have involvement in many organ systems.
Dr. Kaili Stehel:
So pneumonitis, infection in the lungs, in the intestines, enteritis, hepatitis in the liver. And they can be poorly grown, so they can be less in the 10th percentile for their weight, they can have their Ponderal index, or BMI can be abnormal. They can have seizures. So the more permanent sequela, as some of these can persist like the growth retardation and everything, but the more permanent sequela are going to be microcephaly, with the FOC, the head circumference, less than the 10th percentile, vision loss or infection in the eye, chorioretinitis.
Dr. Kaili Stehel:
Hearing loss, which is mainly sensorineural, and they can have those intracerebral calcifications, which would be, again, periventricular versus with Toxo, we'd have diffuse calcifications. Mental retardation, motor disabilities like cerebral palsy, seizures. And then, remember, death is going to occur between 3 and 10% of all infants with symptomatic disease. And, overall, between 0.3 and 1% of all infants with CMV.
Dr. Kaili Stehel:
I just want to spend a minute on hearing loss because that's really the main sequela in CMV. So CMV is the leading non-genetic cause of hearing loss of children in the United States. So, remember, hearing loss in babies happens between one to three per 1000 live births. Okay? And if you fast forward to when they're going to preschool, it's higher, three to five per 1000 live births. So CMV alone accounts for 20% of all that hearing loss. That's a huge proportion at birth. And by the time the kids are in that preschool range, by the time they're four years old, it's a quarter, 25% of all childhood hearing loss is from CMV. And sensorineural hearing loss is the most common sequela after congenital CMV. It occurs in perhaps up to 50% of symptomatic. And even more alarming is that it can occur in 15% of babies that are otherwise asymptomatic. Okay? So you think, "Well, we do newborn hearing screening, universal newborn hearing screenings since the late 90s, so that's no big deal we're going to catch it." So, unfortunately, many babies who are going to develop hearing loss, for that 50% with symptomatic, and the 15% in asymptomatic groups, many of them don't have it at birth. Perhaps, 55% or half of the symptomatic babies that are going to have hearing loss don't have it yet when we screen them for the first time. And it may be even three-quarters, 75% of asymptomatic babies don't have it when we screen that first time.
Dr. Kaili Stehel:
And, unfortunately, 65% of the hearing loss deteriorates over time, so it's not just like you don't have it, and then you get it, and it stays stable. It gets worse. And so we have to develop monitoring systems for hearing loss. It's not enough just to evaluate at birth. We have to do so in an ongoing way.
Dr. Neeta Goli:
Is the sensorineural hearing loss typically unilateral or bilateral?
Dr. Kaili Stehel:
It can be either.
Dr. Neeta Goli:
Okay. And question for you, actually. So if we do not catch the congenital CMV when babies are first born, and then the child develops delayed-onset hearing loss, how are we able to determine whether that's because of congenital CMV?
Dr. Kaili Stehel:
So that can be problematic, so then you require an extensive search. Well, first of all, you might find some evidence for congenital CMV infection. Maybe you have those calcifications like I was talking about, something that would help you know that it was CMV. Maybe it was classic... they could go back, and maybe there was something on prenatal sono. And we've looked back in the setting of maternal HIV and screening CMV, in the setting of an infant who does have hearing loss, and often, as clinicians, we don't think it's CMV.
Dr. Kaili Stehel:
So maybe there was mild thrombocytopenia with platelets less than 150, maybe there was a palpable spleen, maybe there was microcephaly, but perhaps Mom also had hypertension. So subtle things, because, remember, 90% of babies are going to be asymptomatic. So these subtle things, not the obvious baby that has a five-centimeter spleen and a seven-centimeter liver, and tiny microcephaly. So we can look back and see that there were some subtle clues after birth. Maybe they had a CBC for something else, like low temperature, and there was thrombocytopenia.
Dr. Kaili Stehel:
Unfortunately, it can be difficult to confirm if you don't do so within the first two to three weeks after birth, but not impossible. We could rule out everything else and check Mom, check baby with antibody testing. But, ideally, we would confirm within two to three weeks.
Dr. Neeta Goli:
You mentioned some signs and symptoms. So when you're rounding on your babies in the nursery, which babies do you decide to screen for CMV?
Dr. Kaili Stehel:
Okay, so we talked about what they look like when they have infection during the pregnancy. So who would I screen? So let's first think about Mom. So if Mom has HIV, we should check for CMV because co-infection would be much worse for the baby, and also that would be a period that could be, if she were untreated and everything, the time that's immunocompromised, so higher risk of transmission. And then also, the risk factors that put her at risk of HIV would also be some of the same for the CMV acquisition.
Dr. Kaili Stehel:
If Mom has been known or suspected to be infected during pregnancy, whether it's primary or non-primary, maybe she had symptoms, maybe she had the flu, but it wasn't flu season, or maybe she had screening, maybe she was a healthcare worker and particularly worried, so she was known to be negative and became positive, maybe she had an abnormality on her sono. So all of those babies would need to be screened.
Dr. Kaili Stehel:
Okay. So, also, any infant who has microcephaly, so FOC less than the 10th percentile, growth retardation. Whether you'd like to use the Ponderal index or the BMI, but a palpable spleen in the first day, along with the liver, so liver down a couple of centimeters and the spleen tip that goes away, I would let that slide. But if I can still feel it the next day or the day of discharge, then I would check CMV. Thrombocytopenia.
Dr. Kaili Stehel:
We talked about maternal risk factors. And then, also, an infant who doesn't pass the hearing screen, and that would be according to the Joint Committee on Infant Hearing recommendations. Okay, so how are we going to screen? We're going to do PCR of the urine or saliva, and either one is fine. You do not have to confirm that, one with the other, or with a culture, and that has 97% sensitivity and specificity. And we're going to need to do that, like we said, within two to three weeks.
Dr. Kaili Stehel:
So we talked all about CMV already this morning, and you might be thinking, "Well, why don't we do a universal newborn screening?" So the trouble that's been looked at, there was a seven-center study looking at that. There's great interest. I would be in support of that. I suspect that will come along in my career. But the PCR of the blood, that dried blood spot we already collect in babies, so the PCR doesn't work well. It has low sensitivity, so a high false-negative rate.
Dr. Kaili Stehel:
And these days, we don't need to do cultures unless you happen to live in a place where PCR is not available. And then culture of the urine or of the saliva, that was the gold standard for a very long time, and that was, obviously, you could find CMV that way. Antibody testing is not on our list. Remember, IgG crosses the placenta from the mom to the baby, and so that can, if mom has had CMV either during the pregnancy or before, then that would be positive, so that's not going to help us because maybe she didn't reactivate or get reinfected. And then IgM has low specificity, so false-positives.
Dr. Kaili Stehel:
Now, just because we are doing this podcast distanced, I just want to speak for a second about when you have to make special modifications, like with COVID right now. So for a while with COVID, even though our goal is to do the newborn screening and the hearing screening for everybody in the hospital, there might be a situation where you are unable to do that. So then you're going to have to think about, well, if the baby in the hospital, a normal baby with no symptoms, didn't pass the hearing screen, then many places do, in that high-risk setting, recommend and perform a CMV PCR.
Dr. Kaili Stehel:
So if you can't do the screening, what should we do? Should we do the PCR on all those babies? That's going to depend on how common COVID is. Should you not do the PCR, if you can't do the hearing screening, should you wait, mostly, those babies would be seen back at a month, and then it would be too late, outside of that time frame of two to three weeks.
Dr. Kaili Stehel:
So there's different ways to tackle it, you could screen every baby who you can't do the hearing screen on for CMV, or you could wait until the month. And if they were negative, well, that helps you. If they're positive, you're going to have to go back and look carefully where it stuck in. What you were asking about earlier, "Do they or do they not have congenital CMV, did they get this from transplacental passage, or did it come from exposure to secretions at birth, or breastfeeding?" Which the latter two would have no symptoms in a well term baby.
Dr. Neeta Goli:
Okay. If an infant is found to have congenital CMV, what are the next steps while the baby is still inpatient?
Dr. Kaili Stehel:
Okay. So unless the infant is critically ill, nothing needs to be done inpatient. So we certainly don't need to delay discharge in an asymptomatic infant. If the baby is ill enough to be in the ICU, they would require treatment if they had pneumonitis or hepatitis, or enteritis, any of those symptoms. But in the past, in the not so distant past, I would say in the last several years, certainly less than five years, culture was used, of the urine or the saliva, to diagnose symptoms.
Dr. Kaili Stehel:
So most babies that were mildly symptomatic or asymptomatic that were delivered and cared for in the newborn nursery would be discharged before the results would be available. And many centers sent their testing to a few centers in the United States. Salt Lake City would be a common place where CMV culture was sent.
Dr. Kaili Stehel:
But, if an infant were symptomatic, so now we look at getting a head ultrasound, looking for those intracranial calcifications, a CBC with diff looking for anemia, thrombocytopenia, neutropenia. Some of these are from the infection with the virus in utero or some of them looking at what some of the common side effects that the medications can cause, in case the baby ends up being treated.
Dr. Kaili Stehel:
Liver function tests, and then an eye exam, but most ophthalmologists have all their equipment and prefer to do that in the clinic or the office. So if the infant's critically ill, you would want to talk to pediatric infectious disease and talk about treatment options, whether they were very sick, like with IV ganciclovir, oral valganciclovir
Dr. Kaili Stehel:
And if they're CMV positive and they pass their hearing screen, then we would want to re-screen them by three months of age, and then, also, at least every 12 months until three years, or even sooner, depending on the clinical situation because we know that the hearing loss can come after birth or it can worsen if it's already present.
Dr. Neeta Goli:
And then what treatment do we have for babies who are found to be symptomatic?
Dr. Kaili Stehel:
Okay. So treatment started with IV, and it started in symptomatic infants who were in the high risk group for developing cerebral palsy, so they already had CNS involvement. And it was six weeks of IV ganciclovir versus no treatment, and it was shown to halt the worsening of hearing loss because these babies were already symptomatic.
Dr. Kaili Stehel:
The studies went on, and now the recommendation is that a symptomatic infant would be offered six months of oral valganciclovir. And that's because what we're trying to really impact here is the childhood deafness because, remember, CMV accounts for 25% of all childhood deafness. So if we can halt the worsening or prevent it from occurring, that would make a big impact.
Dr. Kaili Stehel:
Currently, a symptomatic infant with CMV, and that, now, these days, doesn't have to include CNS symptoms. They show improved audiologic and neurodevelopmental outcomes when they're given Valganciclovir, the oral. The dose was 16 milligrams per kilogram per dose, BID, for six months. Now, 20% of them develop neutropenia, and that was seen with the IV medication too, and some of the babies have to have a reduction or have their treatments halted. It can be restarted because with neutropenia, you have to weigh the risks versus the benefits.
Dr. Kaili Stehel:
So if the baby needs IV medication, if they can't tolerate PO, maybe they have necrotizing enterocolitis, then we could treat them with six milligrams per kilogram per dose. And they have higher transient neutropenia, about two-thirds of them. So you monitor that with ANC, weekly, for six weeks, and then at eight weeks, and then monthly, and then every other month.
Dr. Kaili Stehel:
So we want to treat, right now, an infant with congenital CMV infection that has moderate to severe symptoms, and we need to be able to start it within one month of birth. If it's a preterm infant that acquired CMV either transplacentally, or even from secretions at birth, or breast milk, or transfusion, we could treat those babies also. And that you might treat for a couple weeks IV and then see if they're improving, and then perhaps a couple weeks more.
Dr. Neeta Goli:
And then, once we discharge these babies, what outpatient referrals will they need?
Dr. Kaili Stehel:
Okay. Because hearing loss is the number one sequela, we're going to work together with audiology, so we're going to follow the Joint Committee on Infant Hearing recommendations. They were last updated just last summer, in 2019, and they really stressed that CMV has a much larger impact than previously recognized on hearing loss in childhood.
Dr. Kaili Stehel:
So we're going to screen all infants at birth, use universal newborn hearing screening, and then re-screen an infant who's CMV positive by three months, and, at a minimum, 12 months or sooner. We talked about ophthalmology's going to evaluate in the period after birth, and then they'll follow along. And the reason that we are focused on the hearing and visual input is that if the child does have neuro-developmental delay, obviously, correcting any hearing loss or visual loss is going to be really important to help the child reach their optimal developmental potential.
Dr. Kaili Stehel:
Okay, so just one more word about hearing loss and the importance. Remember, before we had universal newborn hearing screening, so that would have been the late 90s, the average age of detection of a child with hearing loss was two and a half years, and it didn't matter who they lived with, the pediatrician, because, remember, you will progress. The first notion, really, that you are dealing with hearing loss in your baby is going to be when they don't have a word, so that's going to be around about a year. And then there was some delay.
Dr. Kaili Stehel:
So the average age of diagnosis when there wasn't newborn universal hearing screening was two and a half years. And it is a tragedy because the average reading ability of a child who had a normal intellect diagnosed during that period... so they're graduating from high school and they're normal intellectually, they just don't hear. Their average reading ability was fifth grade. And that really limits the jobs that they can have, the partners that they will meet and marry, and it really negatively impacts their life, so that audiology input is going to be really important for us.
Dr. Kaili Stehel:
So we're also going to want to refer to ECI, the Early Childhood Intervention, the federally mandated program that's run by the state, to help us with intervention part of hearing loss, whatever services in the home and in the school. And then the pediatric infectious disease clinic, and if we haven't already gotten a head ultrasound and labs, we have that arranged.
Dr. Kaili Stehel:
So for us, our pediatric infectious disease clinic at Children's, that'd be Dr. Amanda Evans, has a congenital infection clinic, with Fiker Zeray among others, and they will help us manage these babies and follow them. And they will follow the Texas Early Hearing Detection and Intervention, the one month, three month, six months goal. So screening by a month, confirming by three months, including referral to ECI, and intervening by six months, to include all of the ECI and communication services. And they'll help us with our treatment options.
Dr. Neeta Goli:
And then you did touch on this earlier, but what is the long-term prognosis for these babies?
Dr. Kaili Stehel:
Okay. So if we're going to talk about that CMV occurs in 1 in 100 to 1 in 200 live births, each year, that's going to be about 20 to 40,000 infants born with congenital CMV infection. Like we said, the death rate was between 3 to 10% in symptomatic infants, but 1% of all infections, that's going to be about 200 to 400 deaths per year in the United States.
Dr. Kaili Stehel:
And if you think about hearing loss, and it's occurring in up to 40% of symptomatic babies, and up to 15% of asymptomatic, and that's not even included with CNS sequela, the visual loss, the cerebral palsy, that's 8,000 babies born a year, in the United States, with permanent disability from CMV. And the cost, the annual cost just directly for caring for those babies, is estimated to be between one to two billion dollars.
Dr. Kaili Stehel:
We believe we can make a difference if we have better prognosis if infection occurs after maternal non-primary infection. We have a better prognosis for the baby if it's an asymptomatic infection. We have better prognosis if Moms are treated if a fetus is already symptomatic with IVIG. We have better prognosis if the baby can be treated with valganciclovir.
Dr. Kaili Stehel:
And remember that 90% of the babies are asymptomatic, so they're not going to be in the ICU. I put that in quotes, in air quotes that you can't see on the podcast, but up to 10 to 15% of them can have hearing loss. And to be very careful about the spleen and then about thrombocytopenia, and the FOC that's just below the 10th percentile.
Dr. Neeta Goli:
And then, since we went into CMV, congenital CMV, can you briefly talk to us about postnatal CMV? You mentioned it could be transmitted during the birth process and by breastfeeding.
Dr. Kaili Stehel:
Yes. Okay, so in a well term baby that is exposed to CMV just from genital secretions at birth or breastfeeding, there are felt to be no symptoms, but the same is not true for a preterm baby. So a preterm, very low birthweight baby, so less than 1500 grams, less than 32 weeks, can be symptomatic. And so that baby, or if the baby got a blood transfusion, in the symptomatic setting, they would be treated.
Dr. Kaili Stehel:
But in the well term baby, from breastfeeding or the secretions from the mom around the time of birth, that is what contributes, in large part, to our seroprevalence. After the babies are born, 1 in 100 to 1 in 200, we're going to work our way up to, in some populations, to where 100% of people have been exposed to CMV. And that's how we get it, is from secretions from Mom, breastfeeding, depending on what our childcare setting is and our home situation, and then our sexual practices.
Dr. Neeta Goli:
Okay. Dr. Stehel, thank you so much for joining us today, for taking the time out of your busy schedule to have this discussion with me. To end today's episode, do you have any advice for our listeners while they're taking care of newborns?
Dr. Kaili Stehel:
Yes. I want to thank you for having me. And then I want to remind people to think about how common congenital CMV infection is, and even if you forget all of the numbers, just to think it is more common than all the TORCH infections, hands down, added together, and by a factor. And so think of CMV, think of screening for it in your patients when they have risk factors or if there are clinical signs or symptoms.
Dr. Kaili Stehel:
And then, on a personal level, remember that we can talk about it with our patients and that healthcare workers, unlike daycare workers, don't have a higher rate of seroconversion. When you're thinking about a pregnancy, it's been shown that if you are known to be negative and you have a positive child, and you're highly motivated to reduce your seroconversion with the hygiene recommendations that we talked about from the CDC, that you can make a difference while we're waiting for a vaccine development.
Dr. Neeta Goli:
Dr. Stehel, thank you so much for joining us today.
Dr. Kaili Stehel:
It was my pleasure.
Dr. Neeta Goli:
Oh, do you want to talk about the CMV month?
Dr. Kaili Stehel:
Oh.
Dr. Neeta Goli:
I didn't know about that. I didn't know that was a thing.
Dr. Kaili Stehel:
That is pretty dorky. Did you know that national CMV month is in June?
Dr. Neeta Goli:
I did not know that. That is good to know.
Dr. Kaili Stehel:
Yes. And also, my favorite thing is this graphic that CMV in the U.S. and worldwide is the most frequent but under-recognized cause of neurologic damage. It's more than fetal alcohol, Down syndrome, everything. We talked about the infectious, but it's just amazing, the impact, and somehow I don't feel like that's conveyed to us well. If you don't look, you don't know.
Dr. Neeta Goli:
Thank you so much.
Dr. Neeta Goli:
Thanks for listening to Newborn News. We hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback, or suggestions for future episodes, please, email me at NewbornNews@UTSouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests and do not necessarily reflect the views of the university.