Dr. Sharma: Hello, everyone and welcome back to another edition of Neonatology Review: Isolette to Crib. I'm Dr. Jyoti Sharma, and I will be your host for this episode. The purpose of this episode is to review high-yield common topics in neonatology. While our focus is geared towards the perinatal and neonatal boards, anyone learning or studying neonatology will find this podcast useful.

For this episode, our guest is Dr. Diane Lee. She is a neonatologist with us here at Children's Mercy Hospital in Kansas City, and her area of interest is in the care of the extremely low birth weight infants. She is one of our neonatologists on the small baby unit team. Good afternoon, Dr. Lee, and welcome. How are you doing today?

Dr. Lee: I'm doing fantastic. And hi, everyone.

Dr. Sharma: Dr. Lee is joining us today to talk about perinatal and neonatal cytomegalovirus or CMV infection. In this episode, we will discuss the epidemiology, pathogenesis and clinical manifestations of CMV. Dr. Lee, to introduce this topic, can you tell us what exactly is cytomegalovirus?

Dr. Lee: So cytomegalovirus or also known as CMV is a highly prevalent virus that is actually part of the herpes virus family. And specifically, it is herpesvirus 5. Adults, infants and fetuses can acquire the infection with symptoms ranging from being completely asymptomatic to being severely ill with lasting consequences affecting neurodevelopment.

Dr. Sharma: Thank you for that introduction. Sometimes we don't realize that CMV is part of the herpes virus family of viruses. Can we talk about the incidents and epidemiology of CMV, most specifically its prevalence among women?

Dr. Lee: So the prevalence of CMV among seropositive women of reproductive age is estimated to be about 58% in the United States and 86% worldwide. So this actually makes CMV the most common intrauterine infection worldwide resulting in about 30,000 infants affected each year. The seroprevalence and risk for infection is more prevalent among lower socioeconomic groups in developed countries; those who are in contact with children under three years of age; non-Hispanic, black or Mexican American race and higher parity. And in a systematic review that measured rates of CMV seroconversion, the annual rates of seroconversion among pregnant women is 2.3%; among healthcare workers, it is also 2.3%; and among daycare workers, it is 8.5%, which is very shocking.

Dr. Sharma: I just wanted to add that daycares and preschools are a significant source of infection in pregnant women. And I know we will talk a little bit more about this later. So Dr. Lee, given the burden congenital CMV infection has on an infant's neurodevelopment, are there any antenatal screening for diagnosis of CMV infection for early detection in pregnant women?

Dr. Lee: So Dr. Sharma, actually currently there is no recommended CMV universal screening during pregnancy, especially because most affected pregnant women are asymptomatic.

Dr. Sharma: Dr. Lee, that is true. But some European countries and Israel do offer antenatal CMV screening. So the reasons not to screen include the absence of medication to prevent transmission and the difficulty of predicting sequelae. Some have argued that antenatal screening is useful for identifying seronegative pregnant women and counseling them about personal hygiene practices and hand-washing, but its cost effectiveness is open for discussion.

Dr. Lee: That's interesting, Dr. Sharma.

Dr. Sharma: So can we move on and talk about the microbiology and the pathogenesis of congenital CMV infection.

Dr. Lee: Yes, the CMV virus is a double-stranded DNA virus that is surrounded by a capsid with intranuclear and paranuclear inclusions. So on histology, it actually has an owl's eye appearance.

Dr. Sharma: I do remember this from my microbiology class in med school.

Dr. Lee: Yes, me too. Transmission most commonly occurs through contact with infected body fluids, such as saliva, respiratory secretions, urine or blood.

Dr. Sharma: As we mentioned earlier, daycares are a common source of transmission. Can you talk more about this?

Dr. Lee: So it is estimated that 30 to 70% of children in daycare excrete the CMV virus and infected infants and toddlers can actually spread the virus for years. Also, very interestingly, the virus can survive on fomites for hours, such as on toys in daycare centers and, therefore, female daycare workers are at occupational risk for CMV. And this explains why the seropositivity rate is so much higher among women who work in the daycare center setting.

Dr. Sharma: Again, that is very important information you shared. Moving from daycare transmission, can you talk about transmission in the neonatal period itself?

Dr. Lee: Yes, there are a few different transmission in the neonatal period. The first is CMV transmission can occur during birth while passing through the birth canal in addition to transmission through blood transfusions or even through ingestion of infected breast milk.

Dr. Sharma: Dr. Lee, that is important because CMV can be acquired in the neonatal period as opposed to congenital infection. Let's first discuss more about congenital CMV and in utero transmission. What can you tell us about that?

Dr. Lee: So congenital infection can occur from primary infection or as an reactivated infection in the mother. And overall, only 5% to 10% of congenital infections are symptomatic, And most of which are following a primary infection. The estimated risk of transmission for a primary infection is 30% to 40% if occurred during the first and second trimester compared to 40% to 70% during the third trimester.

Dr. Sharma: So Dr. Lee, does the risk of in utero transmission vary with trimester of pregnancy the maternal infection occurs?

Dr. Lee: Yes, Dr. Sharma. So it's very interesting. So maternal infection in the first trimester has a lower risk of congenital transmission to the fetus. But if transmitted, the risk of severe sequelae is increased if congenital infection occurs during this time.

Dr. Sharma: Dr. Lee, thanks for making the important point. While the risk for infection is lower in the first trimester, if infected, the fetus or the neonate is more severely affected as opposed to third trimester where the risk of infection is higher, but the disease severity is less. So another very important point. Dr. Lee, thank you for that important discussion on in utero transmission. Now, let's move to neonatal clinical manifestations of congenital CMV infection. And starting off, can you elaborate how do we distinguish congenital CMV from acquired CMV in the neonates?

Dr. Lee: So if the CMV infection is diagnosed in the first three weeks of age, that is classified as a congenital infection, whereas if it occurs after three weeks of age, then that is classified as a postnatally acquired infection. And congenital CMV infections is further differentiated into asymptomatic and symptomatic infection.

Dr. Sharma: Dr. Lee, if I remember, most congenital CMV infection in neonates is asymptomatic. Isn't that true?

Dr. Lee: Yes, Dr. Sharma, that is true. So 85% to 90% of all infants with congenital CMV infection are asymptomatic at birth. The most important sequelae of asymptomatic congenital CMV infection is sensory neural hearing loss, which we will discuss separately very soon.

Dr. Sharma: Again, Dr. Lee, thank you for making the distinction between symptomatic and asymptomatic infection. Let's concentrate on symptomatic CMV infection for now. What can you tell us about symptomatic congenital CMV infection?

Dr. Lee: So symptomatic congenital infection occurs in 10% to 15% of infected infants and can present with very severe life-threatening multiorgan involvement. CNS involvement may include microcephaly, ventriculomegaly, periventricular calcifications, cortical atrophy or periventricular leukomalacia. Other systemic symptoms include chorioretinitis, hepatosplenomegaly, abnormal liver function tests and jaundice, growth restriction, petechiae and thrombocytopenia and diffuse interstitial or peribronchial pneumonitis. And the overall mortality is 20% to 30% for symptomatic congenital CMV infection.

Dr. Sharma: Thank you for going over the clinical manifestations of symptomatic congenital CMV. The ones that may appear on the neonatal board include the famous blueberry muffin rash, periventricular calcification as opposed to scattered calcification with congenital toxoplasmosis infection on head imaging. Also, important to know that there are other conditions in which neonates can have blueberry muffin rash.

Dr. Lee: Dr. Sharma, do you know what the blueberry muffin rash is due to?

Dr. Sharma: Dr. Lee, I have to say I do. Isn't it a result of dermal extramedullary hematopoiesis? That's why it usually occurs in conditions where there is bone marrow suppression or failure.

Dr. Lee: Yes, that is very interesting.

Dr. Sharma: Some of these conditions actually include, apart from congenital CMV, that you can have blueberry muffin rash, in other TORCH infections, leukemia and even severe neonatal sepsis. And it's a rash that I think we see maybe once or twice a year in our sick patients in the NICU. Moving to acquired neonatal CMV, is the clinical manifestations similar to congenital CMV in the neonatal period?

Dr. Lee: That's a great question, Dr. Sharma. And for our learners and listeners, it is important to remember that postnatally acquired CMV infection is usually clinically benign or self-limited and does not have the same constellation of symptoms or risk for hearing loss as compared to congenital CMV infection.

Dr. Sharma: Talking about hearing loss, let's shift to hearing loss and neurodevelopmental impact associated with congenital CMV infection. What can you tell us about that?

Dr. Lee: Of course, Dr. Sharma, this is also very important. So hearing loss is the most common congenital condition and affects 3 per 1000 infants born each year. And congenital CMV infection is the most common cause of non-genetic sensory neural hearing loss and learning disability in children worldwide.

Dr. Sharma: That is a very important point.

Dr. Lee: So, although the hearing loss may be present at birth, actually less than 50% of the cases are detected by the newborn hearing screen. Some important remembering points about hearing loss for CMV is that it can be unilateral or bilateral. It can range from mild to profound hearing loss. And most affected infants have progressive hearing loss, which is thought to be due to continued viral replication in the inner ear, which is very interesting. And also 25% of affected infants with congenital CMV are diagnosed with hearing loss by their fourth birthday.

Dr. Sharma: And Dr. Lee, thanks for making such important point on hearing loss. Early detection and management of asymptomatic hearing loss is of paramount importance.

Dr. Lee: Absolutely, Dr. Sharma. So thank you for emphasizing the importance of early detection for hearing loss for our listeners. I also wanted to mention that the Joint Committee on Infant Hearing and the American Academy of Pediatrics has guidelines and timeline goals in regards to hearing So the goal is that for every newborn to have a hearing screen completed by one month of age, a diagnosis of any hearing loss by three months of age, hearing aid selection and fitting within one month of confirming the hearing loss if the parents choose that option and entry into early intervention services by six months of age.

Dr. Sharma: Dr. Lee, you have discussed some very important aspects of the epidemiology, pathogenesis, and clinical manifestations of congenital CMV infection. Can you please summarize the final key points for our listeners?

Dr. Lee: Yes. So some of important points to remember about CMV is that CMV is the most common intrauterine infection worldwide and is also the most common cause of non-genetic sensory neural hearing loss in children. Also, the majority of congenital CMV infections are asymptomatic at birth. However, the most important sequelae is sensory neural hearing loss and the potential neurologic impairment. And lastly, the Joint Committee on Infant Hearing and the American Academy of Pediatrics have guidelines and timeline goals for hearing screening in newborns.

Dr. Sharma: Dr. Lee, before we end this podcast, I wanted to find out if you came with any questions that we can discuss?

Dr. Lee: Yes, Dr. Sharma. I have two questions for you and for our listeners. So the first question is: The most common intrauterine infection affecting newborns is most likely to present with, A, vesicles on exam; B, intracranial calcifications;. C, hearing loss; D, pancytopenia from bone marrow suppression; or E, coagulopathy and DIC?

Dr. Sharma: Wow, Dr. Lee, this is such a good question because it requires a lot of thinking. So I know, in your presentation, you mentioned CMV is the most common cause of intrauterine infection and the most common sequelae or manifestation of CMV infection is hearing loss. So the answer here is C, is that correct?

Dr. Lee: Yes. Dr. Sharma, you are correct. The answer is C, hearing loss. And CMV may present with intracranial classifications and other things such as coagulopathy and DIC in very ill infants. But the take-home point is hearing loss is caused by CMV.

Dr. Sharma: Do you have another question?

Dr. Lee: Yes. Question two: A healthy term infant is ready for discharge today from the newborn nursery. Upon reviewing the chart, you see the infant failed the newborn hearing screen twice during hospitalization. What is a risk factor for the etiology of the infant's hearing loss? A, the mother is 18 years old and this is her first baby; B, the mother reports frequently eating shellfish throughout pregnancy; C, the mother reports working in a daycare; or D, the infant is formula-fed only.

Dr. Sharma: Okay, so this one is focusing on the mother. And I think we covered in our podcast just now that if a mother is working in a daycare and is seronegative, she is at risk for CMV infection during pregnancy. So the answer is C, the mother reports working in a daycare. Is that correct?

Dr. Lee: Yes, that is correct, Dr. Sharma.

Dr. Sharma: Dr. Lee, thank you so much for participating in this podcast and sharing your knowledge and wisdom with all our listeners. And thank you everyone for listening. Our next podcast will focus on perinatal and neonatal CMV evaluation and management. Until next time, this is Neonatal Review: Isolette to Crib. Happy listening.