Sammi: Good evening everybody and welcome to this evening’s Congenital CMV: Common and commonly missed webinar. My name is Samantha and I am your host for this evening. Before we jump in, I just want to make a quick Acknowledgement of Country. We recognise the traditional custodians of the land and sea on which we live and work, and we pay our respects to Elders past and present.

So in saying that, I would like to introduce our presenters for this evening. So we are joined by Dr Bill Rawlinson and Dr Tim Senior. Bill is a clinician scientist recognised internationally for translational research into human CMV in pregnancy and other immune compromised clinical states. He is a medical virologist who has established overseas serology and virology clinical research programs, state-wide transplant donor screening and national quality programs for serology and biosecurity. He is conjoint Professor at UNSW diagnostic and clinical virology of a range of virus illnesses.

 And Dr Tim Senior. Tim is a GP at Tharawal Aboriginal Corporation in South Western Sydney. Tim is also an RACGP medical advisor for the national faculty of Aboriginal and Torres Strait Islander health and a senior lecturer in General Practice and Indigenous Health at UWS. So, thank you Bill and Tim for joining us this evening.

Tim: Good evening to you, Sammi.

SammiAnd I will hand over to you now Tim to take us through the learning outcomes for this evening and then we will hand over to Bill to go through the presentation.

Tim: Lovely. Thank you very much. Good evening to you all. So, the learning outcomes are just educational-speak for what we hope to achieve for this evening. So by the end of this online activity, you should be able to explain to patients how mother to child transmission of viruses occurs with a specific focus on congenital cytomegalovirus (CMV), including how often this occurs. You should be able to discuss preventative steps that can be taken to help reduce the risk of exposure to CMV. We should be able to identify circumstances in which testing for CMV is appropriate for pregnant women and for neonates, and know which tests to order. And we should be able to diagnose patients and make appropriate referrals to specialists discussing under which conditions that is required. So, we are going to achieve all of that tonight and finish on time. Without further ado, I shall hand you over to Bill and if you do have questions as we go through, I will keep an eye open for those and at various points if I get the chance, we will ask those and see what answers we can get. Thank you very much, Bill.

BillLook thanks very much Tim, I really appreciate that everybody is here tonight because this really arose out of a discussion we had internally as well as with New South Wales Health, about what people know about congenital cytomegalovirus, and I guess if anything comes out of tonight, I would just like people’s awareness to be raised, because all the evidence is that not only specialists, other clinicians, GPs, but also pregnant women, really know little about congenital cytomegalovirus and given that it is the most common cause of congenital malformation, second only to cerebral palsy, we regard this as something that really awareness raising is very important. Just a brief acknowledgement, and then I thought I would like to just talk a little bit generally about how viruses get from mothers to their foetus, to their unborn baby, because I think it does bare upon how we think about prevention and how in the future it is likely we will have other forms of prevention. It is important to realise that when we think about the foetus, that it is an immunocompromised person, that in many ways, as the foetus grows through the first, second and third trimester, things change and so, it is really that maternal immune suppression which allows reactivation of latent viruses like CMV. I guess, the second kind of general comment before we get into a bit more detail is that really, we are talking about a blood-borne virus and so, things like herpes simplex, even HIV, transmission is often mainly at the time of parturition, at the time of birth. Although, when we are talking about CMV, we are talking about transmission across the placental barrier and this is just a schema of what a placental villous looks like, and really it is that blood-borne transmission that we are talking about. So, I am going to talk a little bit generally at the start about viral infections and congenital infections in particular, a little bit about diagnosis and then really focus on congenital cytomegalovirus which I will abbreviate as CMV.

So, the types of infections. Really this may be very simple for all of you, but I guess it just provides a basis from which to think. Really, if you are thinking about acute infection, something like a rhinovirus, cold, like SARS, coronavirus, if you are thinking about things that cause acute infections, they do not persist. They often cause disease, so if you have a rhinovirus, you usually have symptoms of a cold. They typically transmit horizontally, so they do not co-evolve with the host. And they are very dependent on a host population structure. So if you have measles for example, in a non-immune population, it will spread very rapidly. And so this is an example. This is hand foot and mouth disease. This is a slide of an ulcer in a patient with enterovirus infection and of course this is an example of microcephaly due to Zika virus. Even though Zika virus causes neuronal malformation, it causes long term neural damage, it is an acute infection. So it comes, it causes the damage and then it goes. What we are going to talk about tonight, is cytomegalovirus, which is a type of herpes virus which has a persistent life strategy, and it is very important because most CMV infection and most problems that we see, are a result of reactivation. And this is because CMV establishes latency. That is, once you are infected with it, like other herpes viruses, it persists in the individual host for life. Often acute disease is unapparent, so if a pregnant woman has first episode CMV, only about one in two, perhaps less have any symptoms at all and reactivation CMV during pregnancy is usually asymptomatic. These are highly species specific infections. They do not spread from animals to humans. CMV is a human virus. They co-evolve with the host and they are often from parent to offspring. So they are often sexually transmitted.

This is another example of a latent herpes virus. This is herpes simplex virus, spread to a neonate, and of course herpes zoster and shingles which you are all familiar with, which is of course reactivation of varicella zoster virus.

So, of congenital infections that we see, cytomegalovirus is by far the most common. There are others. Hepatitis B of course can be spread from mother to baby. Hepatitis C, less frequently as well as the others shown there. Influenza virus can spread across the placenta. Although given the millions of cases of influenza every year, transmission is very infrequent. Of course something like parvovirus B19, which is an acute infection, can cause damage to the foetus with hydrops fetalis is common but does not persist in the host. So really, cytomegalovirus is by far the most common.

Again, just a bit of general background. We are talking about transplacental transmission as shown here as spread during pregnancy from mother to child. CMV importantly can be spread by breast milk and probably about two thirds of women who have a baby, will actually have CMV in their breast milk, so it is almost a normal event. Where it is more of a problem, is in very pre-term infants. And of course infection can spread during delivery, that is not really a problem with congenital CMV.

The outcomes of all these viral infections in pregnancy vary, and they vary with timing. They vary with the type of virus. They vary with the amount of virus. But of course some of the outcomes can look the same even though they are due to different viral infections. And so just a few examples of this. So, jaundice, a baby presenting as shown in this slide where the baby has clearly got a big liver and a big spleen. He is jaundiced. He is on phototherapy. That can be most commonly due to cytomegalovirus, but it also can be due to things like rubella, HSV, toxoplasma, syphilis and hepatitis B. In Australia, by far the most common is cytomegalovirus. Just to give you an idea, we have a congenital infections clinic at The Royal Hospital for Women, where along with maternofetal medicine and paediatric specialists, we see congenital infections. We might see two or three women with possible or definite toxoplasmosis a year. We will see somewhere between two and five women with congenital CMV every week. We will see somebody with questionable rubella and do testing on them, maybe once every six months. In Australia there is an infant born with congenital rubella about once every five years, whereas in Australia there is an infant born with congenital CMV once a day.

Other manifestations that often go with jaundice of course are hepatosplenomegaly, purpura and often these are due to the same infections as shown here. Eye abnormalities, less common, but cataracts particularly due to rubella, but as I mentioned in Australia because of vaccination rubella is a rare disease, but also can be due to varicella zoster, toxoplasmosis, cytomegalovirus, herpes simplex. Other eye manifestations like chorioretinitis also occur with the same kinds of infections and glaucoma, keratoconjunctivitis, microphthalmia, much less common. Orthopaedic signs very uncommon now, classically of course due to syphilis, and congenital heart disease due to rubella typically but also due to CMV and possibly due to mumps.

One of the other, I guess major problems and major concerns with congenital CMV and with any congenital infection, neurological disease, and these can be due as I mentioned to CMV but also to herpes simplex, varicella zoster, enteroviral infections. And so, just some examples. This is classical parvovirus B19. It looks like to a virologist like me, this looks like a bit of a red rash. Paediatricians regard this as a sort of a lacey diagnostic type of rash. Classically occurring a couple of days after the facial, the classical slap-cheek syndrome. Parvovirus B19, relatively common.

Rubella. This is an example of rubella, the rash and the cataract shown on the slide here. And really this is a number of notifications and hospitalisations due to rubella and congenital rubella syndrome. And basically once vaccination became universal, fortunately in Australia rubella largely disappeared as a disease that we see.

Enteroviruses. Very common infection, but generally does not transmit from the mother to baby and generally does not cause a problem. So, probably hundreds of thousands of enteroviral infections a year, some of which occur in pregnancy so very frequent. Very frequent coloniser of the gut. However placental transmission is really quite rare, and so very small numbers of enteroviral congenital infections. And of course, Zika virus has been in the news over the last few years. Really in this country not been diagnosed, although of major concern. The major issues around Zika virus are in, have been in South America, and basically the concern has been with microcephaly, intrauterine growth restriction or IUGR, as well as longer term neurological disease.

So, on to diagnosis of congenital infections. Often when we are looking at a congenital infection, we are looking at the end stage. So as I mentioned, congenital CMV is really very infrequently symptomatic during pregnancy and so often the diagnosis is not made until the baby is born. The baby may be born early, microcephaly, small for gestational age, unexplained findings, particularly unexplained neurological findings, unexplained jaundice. And really, at this stage in the neonate it is really important to think about infection. The types of specimens that are taken. I think in summary, in many ways the more the better, but it is very important to try and get to the source of the infection, so throat swabs are very useful for viruses, particularly for CMV, but also for things like enteroviruses and for example herpes simplex. Urine is very useful for CMV and it is often very important to look at the placenta. Often of course, the placenta is discarded. Often they are buried under a tree to allow that tree to grow, sometimes taken home and put in the freezer, but if you are fortunate enough to have the placenta, and there is suspicion that the neonate has a problem, then it is very useful to have that examined, to do molecular testing and to do histopathology. And then there is a list of other sorts of things that are used for specimens, like neonatal serum as well as CFS clearly if there is neurological disease and it is appropriate and also stool. It is very important not to ignore that we do have the benefit in the neonate of the mother, and so where taking blood from the baby may be difficult or the parents may be reluctant, it is often very good to test the mother, and think about serological testing, particularly for things like herpes simplex, but also for things like cytomegalovirus. And so the sorts of tests we would typically do would be serology, most tests are now done using enzyme immunoassays, and for things like CMV, EVV, we do IgG and IgM tests and increasingly we do what we call IgG avidity which basically looks at whether the avidity is low, if it is low, then there is usually infection within in the last three months.

The other important thing of course is if infection is suspected during pregnancy that we go through amniocentesis. Clearly this is as you know an invasive procedure, it has a low risk of things like miscarriage, it has an extremely low risk of transmission of the infection if for example the mother has primary CMV, then amniocentesis really very rarely does transmit and the benefit of course of amniocentesis, is we can directly sample what is basically foetal urine. And that allows us to do nucleic acid testing, abbreviated here as NAT, or quantitative nucleic acid testing to give an idea of how much virus is there. We very rarely culture amniotic fluid for viruses any more. It is clearly useful for bacterial culture, but as a diagnostic test in virology, we really only do nucleic acid tests, typically like polymerase chain reaction, or PCR.

Of course if the baby is born, then you have tests that you can do at birth that include as I mentioned things like throat swabs, stool, where indicated CSF, but often a baby is not diagnosed until after a period of time, sometimes weeks, sometimes months. And things such as congenital CMV if you want to know that transmission occurred in utero, then the diagnosis needs to be made before 21 days of age. In those cases we can go back to the Guthrie card, to the dry blood spot. Unfortunately that has a lower sensitivity and it can miss up to a half or so of effected infants and so ideally, if we can we try and do tests early on. It is also important that most CMN and congenital CMV in Australia is actually undiagnosed and so I said at the start that it is very important that really we try and raise awareness and become aware of CMV because through awareness, not only amongst health professionals, but also amongst parents and pregnant women in particular, then that awareness tends to make people think about it and where a baby is born pre-term or where a baby is small for gestational age, that baby is more likely to have appropriate testing. And this is just a sentence, or a couple of sentences from a woman I saw. I asked her if I could use them and she said yes. And this is basically a woman who underwent routine observation during pregnancy, had an ultrasound, had a fairly non-specific finding which is echogenic bowel on ultrasound that I am sure man of you have seen, and following on that, echogenic valve can be an indicator of infection, in particular congenital CMV. She then went on to testing and unfortunately she in fact ended up having an intrauterine death. And so this is the kind of parent that I really, I guess drives me to raising awareness of congenital CMV, because such a lot of women and as I say, such a lot of health professionals do not discuss congenital CMV. It is not part of routine screening. We screen for things like HIV, hep B, rubella, hep C, syphilis and of course some practices for group B streptococcus. But CMV screening is not part of our current screening algorithm in pregnant women.

So now on to congenital CMV and particularly talking about the problems and particularly talking about diagnosis and maybe questions that are around that. And I guess, you know, the consideration about when testing should be done because in many of these questions it is really a matter of ideal testing or I guess opinion about testing, because at the moment we have a series of tests. If we had one simple test, which we could all do and was very cheap and 100% sensitive and specific, then I guess I would not be talking to you tonight.

So just to reiterate, congenital cytomegalovirus is the most common infectious cause and second most common overall cause of congenital malformation in Australia. And I think if there is any message that I would like you to take home tonight, that is it. I think, if you think it is common, then you will think about it. And these are just some of the numbers. If you look at cerebral palsy, there is around 600 to 800 babies born with cerebral palsy every year in Australia. Some recent studies which have been supported by the Cerebral Palsy Alliance have shown that probably about 10% of those neonates actually have cerebral palsy due to congenital CMV. But if you look, and these figures I think are from about 2015, if there is about 300,000 live births a year, then there is around 350 to 450 of those live births with congenital CMV, and that infection may occur in this figure I have shown, at a standard infection rate of around about 0.6%. That means there is around about 2,000 babies born infected every year, but only a proportion of those are affected. So the majority of babies born with congenital CMV will not have evidence of the disease and we would regard them as completely normal. So, that is where the figure of one a day comes for congenital CMV infants born every day in Australia. And again, to put it in proportion, that is greater than the number of infants born with Down syndrome. That is probably about somewhere between 50 and 100 fold more than infants born with toxoplasmosis, and we are very interested when you look in people’s practices and when you ask pregnant women, you know, what infections do you know about? They all know about rubella, and that is important. They have been vaccinated. But there is one congenital rubella case every five years. They all know about not handing parturient cats and do not change the kitty litter. There is probably about five to ten infants born every year with congenital toxoplasmosis. When you ask them about congenital CMV, and we have done this, we have done some studies, only about one in ten, to one in twenty have ever heard of congenital cytomegalovirus, and the majority of them do not know how to avoid it. And so what we are going to talk about is really some of the ways to diagnose it and some of the ways to avoid it.

And this is just for those who are more visual. If you look at CMV, it is the most common infectious cause, that is the white circle about one in 150, Down’s syndrome about one in 660, spina bifida 6.3 in 10,000 and toxo 0.17 in 1,000. I mean, the point is that this is massively more common than other things, which are very important and it is important to recognise, but which are far more known by the pregnant population and far more talked about by doctors. And that is published evidence, it is not just opinion.

To put this in another proportion, this is from a paper of about 2004 by a guy called Mike Cannon who works at the Centre for Disease Control in the US, and this is looking at the US population. On the right are congenital CMV disabilities compared to other disorders like amino acid disorders, fatty acid oxidation disorders and haemoglobinopathies. Far more common. Importantly of course, we now screen for congenital hearing loss and that is shown here as hearing disorders, and that is done nationally on every infant. About 10% of those infants will actually have their hearing loss due to congenital CMV.

This is some data from the Australian Paediatrics Surveillance Unit, and what this is just looking at, is acute CMV and symptomatic CMV. This is over a period where we have been sampling paediatricians, and this is between 1999 and 2016, and what it shows is the number of cases being reported. I have mentioned that we think 350 to 450 nationally, and yet with a national surveillance program, we only see around 30 to 40 reported every year. So clearly, 90% of infants with congenital CMV are not being reported, and the majority of those in fact are not being recognised until later in life. And some of those, in fact a considerable proportion of them on the basis of some of our data, are not being recognised ever during their life. This figure that has just come up is just looking at the number or the percentage of these infants who receive antivirals. Antivirals need to be given early on. I mentioned that the diagnosis needs to be made before the age of 21 days, but in fact we also need to give antivirals before the age of 21 days and ideally as soon after birth as possible. And what this shows is even though we are seeing only a slight drift up in the number of cases reported, of those cases reported we are seeing more of them treated with antivirals. Now, we do not treat all infants with antivirals. The evidence is that the only benefits that we are seeing in the published data are in infants with neurological disease. And so, really it is important to think about treatment, but it is also important I think to take expert advice and that is what I do, that is why I work with paediatricians, because we discuss every case where antivirals are being considered.

I guess another point is childcare. We recently did some work in childcare looking for CMV and looking at day care centres, and this is a forest plot which many of you will be familiar with, but basically if you look these are a number of studies over the last 30 years or so, and these are looking at childcare and they are looking at whether there is an increased risk of CMV in children attending day care centres, and quite clearly there is. It is something like around a two to three fold increase risk. And that is because children with CMV whether they are infected at the time of birth or later, tend to excrete CMV for several weeks to several months and children with congenital CMV may excrete it for years in their urine and of course with intimate contact with each other through saliva as well as urine, then spread of CMV can occur.

I mentioned previously that hearing loss is due to congenital CMV and these are a number of papers that have been published over the last 10 or so years. The one on the top right from Dahl is the LOCHI study which is a Melbourne study. They show that 8% of hearing loss in the study that they had ongoing was due to congenital CMV. Other studies have shown figures around 5%, and others have shown figures as high as 15%. That is probably too high. Our study which came out this year, we found 6%. And that is in neonates with congenital CMV and hearing loss. And so that is post universal newborn hearing screening program, the SWISH program.

So what are the other problems that arise? I have mentioned hearing loss. That is probably the most common problem. Things like hepatosplenomegaly and jaundice. Microcephaly is relatively uncommon fortunately. Prematurity is a significant part of congenital cytomegalovirus and of course the problems that come with pre-term birth associated with lung and other illnesses, occur in this population as well on top of which they have an ongoing viral infection, and so they can do worse. Eye disease, developmental disability, and probably in about 2% to 5% of infants with congenital CMV, they die in utero, so intrauterine death and stillbirth. So, as I mentioned, just to reiterate, the majority of infants actually do not have any of these things, so the majority of those 2,000 or so infants born every year in Australia do not have these problems, but a proportion, something like 350 of them, will have one of these problems, most commonly hearing loss but also things like neurodevelopmental disability. Stillbirth, we have looked at stillbirth and somewhere around 5% to 10% of stillbirths that are otherwise unexplained are probably a result of congenital CMV. I mentioned pre-term birth, which is also a relatively common condition, also due to congenital CMV and intrauterine growth restriction also due to congenital CMV.

Sorting these out and sorting which ones have a cause such as congenital CMV can be very difficult and so we really do not have accurate figures for these on Australian infants. What we do have are the hearing loss figures and I showed you the figure of 5.9%. These are the data on which we based it, and down the bottom is the age in days. We did this study without additional resources and I guess what I am trying to show is that it can be very difficult to do things like nucleic acid tests and sampling of urine and sampling of saliva in neonates, unless you have some additional resources. This was done just using the existing audiology resources and it is still possible. I guess it is important to realise that unless we do start thinking about it, we are not going to be diagnosing congenital CMV. However it is also important to realise that once we do start thinking about it, we are going to have to think about the downstream consequences of things like notifying parents, of counselling, of follow up, of additional follow up of the infant as well as of the parents.

I mentioned the lack of awareness and this is from a paper that is also just coming out. These are Australian data and Antonia Shand is a maternal foetal medicine specialist at The Royal Hospital for Women. Samples done around 400 women and asked about conditions in pregnancy like rubella, did they know about toxoplasmosis, did they know about syphilis? 90% of women knew something about rubella and it was something appropriate. Almost all of them knew about Downs syndrome. They all knew about HIV and hepatitis B pretty much. Only about one in what is that, about one in six or one in seven women had even heard of cytomegalovirus. The majority of them really did not know anything about it. And they did not know how to avoid it. And I think you really cannot avoid an infection, you cannot do something about it, unless you are aware of it, and then you can go to somebody appropriate such as your GP, such as your midwife if you have been delivered or your obstetrician, and ask them about it and get the right information. So, that is meaning that six out of seven women have not even heard of congenital cytomegalovirus infection, the most common infection and yet, you know, nine out of ten of them have heard of rubella. Not that it is not important to know about rubella, but it is just not a common condition any more. And so along with the Congenital CMV Association of Australia, we and others have been trying to put together pamphlets put together posters, put together awareness and in fact if you give the population of women that I have just shown you, this leaflet that is shown here which is one that Congenital CMV Association and Cerebral Palsy Alliance have put together, then you can improve their understanding, not only their awareness but also their understanding of congenital cytomegalovirus, things like transmission, you know that you can spread it through saliva, well then obviously they are not going to share spoons and food and nick dummies from their older children who are in day care when they are pregnant. They are going to understand things like the risk of salivary spread, they are going to understand things like handwashing and changing nappies. And the red columns here are after reading, a very simple document. These were women who were in the Eastern suburbs, so a reasonably educated population but also populations from elsewhere who had a lesser, a lower educational level, and really they understood it very well, and I guess it is all of our experience that if women can do something, if parents can do something to prevent damage to their unborn baby, they really are very willing to do it. And if it is just as simple as reading a leaflet then they are willing to do it. I would add that these improvements following reading the pamphlet, were measured two weeks after they were given the pamphlet. They were not measured immediately after, that would be cheating. But they really persisted for at least a couple of weeks. And as I mentioned, the pamphlet was given to them, they were shown it, they read it briefly, it was about a five to ten minute interaction, it was not extensive discussion.

This just hows the percentages as a table, and this is knowledge about transmission. This is in a total of 740 women, and the knowledge that these women had after they had read some of the data.

So how do we diagnose congenital cytomegalovirus infection? I mentioned previously that it is good to have specimens, but particularly urine, particularly a throat swab, because cytomegalovirus is shared in saliva. And hopefully where it is suspected at birth, that the placenta is kept and tested. I think the other thing that is important is that, I have not mentioned, is that primary infection with CMV, so infection for the first time in pregnancy has about a one in three transmission rate from the mother to the baby. Something like 60% of pregnant women have had infection in the past. Those women can reactivate during pregnancy. Reactivation of congenital CMV is very common, sorry reactivation of cytomegalovirus during pregnancy is very common. However, transmission is a low event. So only about 1% or so will transmit. However, because reactivation is so common and because 60% of women have had infection before, and because first infection during pregnancy is relatively uncommon, that low rate produces about as many cases of congenital CMV each year as does primary infection during pregnancy which has of course the higher 30% transmission rate from mother to baby. It is also important to mention that in neonates when these specimens are taken, unless the baby is infected, then they should not be excreting CMV in their urine or in their saliva. So these specimens should be negative and so long as they taken sufficiently distant after birth, so a day or so, then they should not have contamination from maternal cervical material or other things which, other mucus that can contain CMV.

When to test and what test to use. So, this is, I guess there are two things. We have talked about neonates. It is I think an easier discussion in neonates than infants, because if a neonate has hearing loss, then it seems pretty obvious that they should be tested for congenital CMV particularly if somewhere between 5% and 10% of those neonates with hearing loss actually are known to have congenital CMV. It is slightly harder in prematurity, small for gestational age, where there are larger numbers. Although if a diagnosis is not made, then it is useful to know whether a premature baby is due to congenital CMV. Unexplained illness really relates to the things that we talked about before, things like jaundice, hepatosplenomegaly or an appearance of the neonate that would be consistent with that. And as I mentioned, testing ideally is before 21 days of age because once the neonate contacts other children, particularly in a setting where that child may be in childcare, then the neonate can often acquire CMV postnatally. And as I mentioned, testing of the Guthrie card, testing of the neonatal blood screening card is only sensitive in about half to about two thirds of infants.

Testing of pregnant women is a whole different issue. It is hard to make concrete recommendations and last year we and others published some guidelines which said universal screening of pregnant women currently is not recommended. There is a whole lot of reasons for that. The test that we have definitely very good, so serology IgG is very good at identifying previous infection, but the IgM test is often falsely positive in pregnant women so it becomes difficult to identify recent infection with that high risk of mother to child transmission. IgG avidity is useful because it does sort out whether infection is in the last three months. But of course this does depend upon the mother presenting for antenatal care, and we do know that the higher risk women in fact are those who do not have antenatal care, who are younger, who have had previous risk activity, may have had a previously sexually transmitted infection, may have other infections. And so, the population where the risk is higher, is actually those where serology can be very difficult.

Testing using nucleic acid testing or PCR is plasma is useful if the pregnant mother has a recent infection, but often that plasma positivity for CMV only persists for a few days to a few weeks. So really, you have got to get them at the time when they are viremic and in fact as I have mentioned, only about half of them have any symptoms. So the whole issue around screening of pregnant women is a difficult one and at the moment we think that raising their awareness is very important. We think that considering testing of infants who are at higher risk of congenital CMV is important and we think that considering whether universal screening of neonates for congenital CMV should be discussed. But what we need is really a sensible discussion around that and around screening of pregnant women. I guess the other issue is that just simply knowing that you are at risk of congenital CMV in a pregnant woman, means that the reality is that if they do something, if they know that they are at risk, they will do something about it. They will not share food, they will stop licking the dummy that might have fallen on the floor. They will wear disposable gloves when they change nappies. Maybe not every time, but by reducing their exposure they reduce their risk of acquisition of CMV, both for the first time as well as reinfection. And the published data are that 40% reduction in transmission to pregnant women occurs just with these simple things.

So just to sort of put that in context, you raise awareness of pregnant women. If they know they are seronegative and at risk, then that is good but they do not have to. If you just raise their awareness and give them some guidance in how to reduce transmission of CMV from the toddler when they are pregnant, and that is the classic sort of patient that we see is a woman who has got a toddler in childcare and is pregnant with their second child. So if they just know about it, they stop, they stop sharing food, they stop kissing on the lips, they wash their hands after changing nappies, they use disposable gloves when changing nappies, they do not co-sleep. Then they reduce their risk of acquiring CMV from their toddler when they are pregnant by 40%. So again, just to summarise in pregnant women we do not think universal screening at the moment is recommended. We do think it needs to be researched and we need more data. We do think increased awareness in pregnant women will reduce the incidence of congenital CMV. We do think in infants who are at higher risk, particularly those with hearing loss, that testing should be undertaken routinely for congenital CMV and we do think that in other infants who have higher risks such as prematurity, it should be considered that whether CMV testing is done.

So this is a fairly spectacularly complicated slide, but it is really, these are really the data that were published a couple of years ago again by Mike Cannon, that we were involved with. This is looking at the US. So they have four million live births and basically just to summarise, the green squares and the blue squares are the number of infants born in the US who would have good evidence for improved outcomes if we screen neonates with hearing loss. And so the point is, you can do these numbers and you can come up with significant numbers of infants who would benefit from screening, either because they had hearing loss at birth or they had delayed hearing loss.

So what do we want to do now? Well, I have mentioned about the issue around screening of high risk infants. I have mentioned about the questions around screening of all neonates, so universal neonatal screening. There is some benefit in that, although that clearly has to go through a far more complex process of discussion in terms of health economic costs. There has been modelling that suggests it is useful. I mentioned antivirals previously. Certainly in most neonates with congenital CMV, antivirals are not of use. However in neonates with neurological disease, there is a paper from a couple of years ago and there is a more recent paper from US groups which quite clearly shows some benefit in giving antivirals early in infants with congenital cytomegalovirus and neurological disease. Just treating hearing loss, there is no evidence for that and currently there is no vaccine available. There have been trials now about eight or ten years ago in pregnant women that showed about a 50% vaccine efficacy for a vaccine that was available then. So there have been trials, but unfortunately at the moment there is no routine vaccine available and there is no vaccine available in Australia.

Control antenatally and around the issues of testing pregnant women. Really there are some things that have clear benefit, prevention, so hygiene, things I have mentioned, not kissing on the lips, not sharing food, not sharing dummies, washing hands after changing nappies, wearing disposable gloves during changing nappies. They are a clear benefit and there is a low cost. And in order to do that, increased awareness in pregnant women has a clear benefit. There is a clear benefit too, of increased awareness amongst healthcare workers. However, currently screening pregnant women is not recommended and as I mentioned, there is no vaccine available in Australia although there have been vaccine trials in the US. And it is likely within the next five years or so, that vaccines will be available. So there are some things that we can do about antenatal control, although they are really around very simple things like hygiene.

And this is the poster that I mentioned that Congenital CMV Association Australia and the Cerebral Palsy Alliance have put together. The hand out trifold that I have shown previously. This is a poster and it is really designed to suggest the simple things that can be done, and I guess people often focus on hand washing, but really the most direct transmission is things like kissing on the lips and sharing food where saliva which may contain CMV in the toddler can be transmitted via saliva to the pregnant woman.

So, just to summarise, this is really what you have already heard. I guess high risk behaviours might sound a bit reminiscent of other things. I guess what we are talking about is other things like high risk of saliva exchange and we did see that women who had more information had improved knowledge. Screening needs a lot more discussion. Hygiene recommendations are really quite obvious and there are new treatments and studies in new treatments that we need.

This is just a case. I do not think we can really do this interactively, but I guess this is just the kind of woman that I suspect that some of you have seen, that I have certainly seen in our congenital infections clinic, somebody who has childcare contact and in this case a childcare worker, and the question was around primary CMV. I have mentioned that primary CMV infection has about a 30% transmission rate from mother to baby. First trimester because that is when infection in the foetus will cause the worst disease, particularly neurological disease, and the sort of confirmatory tests that we might do are listed there. CMV antibodies in the baby, testing the saliva, using a nucleic acid test like PCR, in the past we would have done viral culture but not now. Do you wait? The fourth one is do you test the mother’s blood? The fifth one, do you test the baby’s urine? And do you run a TORCH screen? I guess the things that I would do would be ideally, to test the baby’s saliva so number 2. I would do a PCR on the saliva and also number 5, do a PCR on the urine, and the serology in this setting really is not a whole lot of use. We specifically chose a childcare worker because they are exposed and it is very interesting. I have seen childcare workers who have been working in childcare for five years, in one case for 12 years, became pregnant and had a primary CMV infection during pregnancy. I mean, just almost unbelievable that they had not acquired CMV during that five or 12 years of childcare work.

There have been a couple of cases which have been in the newspapers about 10 years ago of childcare workers who were said to have had a primary infection and an infected neonate, and after that time childcare workers were tested for CMV if they were IgG seronegative, then they were typically not working with less than two-year-olds or they may have been working in more administrative areas whilst they were pregnant. To my knowledge that was done for about five years but is not always part of childcare worker screening. One thing that we think is important, is that in childcare, there is information about spread and about urine and salivary spread from infants and certainly in childcare workers that the facilities consider pregnant women and their risk of acquiring not only CMV of course, but also things like enterovirus from less than two-year-old infants, culminate that need for the childcare worker by having them work somewhere where their risk is lower.

So where to from here? I guess what I hope to have said to you is that there are some simple things we can do in terms of awareness. There are some simple things that we can do in terms of awareness not only for the pregnant woman, but in the neonates at higher risk and making people who are working with them, audiologists, GPs, midwives, obstetricians, specialists aware of CMV and organisations like the Congenital CMV Association Australia have a CMV month which is June, and this was their sort of program for that month to stop CMV. The Cerebral Palsy Alliance has put together a video which is online and really this is very much as I mentioned around awareness.

So, that is what I have to say and I really thank you very much for attending and I am happy to talk about questions or anything else from here.

Sammi: That is great, thanks Bill. I might hand over to Tim, because I can see there are quite a few questions that have come through from our audience. Tim, do you want to go through some of those?

Tim:I am going to fire some questions at you, Bill. Some of these will clarify points that have been covered. So we have had a few questions come through about pre-conception care, antenatal care. So if someone has a positive CMV IgG, and they are planning on getting pregnant, are the sort of recommendations that you give the same around the hygiene that you are giving for women who are pregnant?

Bill: Yes, look it is a great question. I touched upon that. So if somebody has IgG to CMV, that means therefore that they are immune and they have had it before. I mentioned that reactivation does occur in 1%. We cannot really identify those women, but what we can do, is say to them that they should avoid acquiring CMV. So really it is the same hygiene awareness, the same hygiene practices as in a seronegative woman, because we believe that reacquisition, reinfection is important also in those women who are IgG seropositive.

Tim:Yes, excellent. And are the recommendations similar for childcare workers who are thinking about getting pregnant?

Bill:Yes. I think the childcare worker, I think there are a lot of questions around that and as I mentioned, the quite prominent cases about 10 or 12 years ago raised awareness and that has kind of dropped back. Childcare workers are at risk, but of course mothers of toddlers are at risk also because they have that intimate contact with children that often childcare workers do not. I do think that awareness amongst pregnant women should extend to include childcare workers. I guess the question is, are they particularly different? The issue is that they are working in that setting and if they are intending on becoming pregnant then it is useful for them to know their seropositivity status and I think it is important for them to let their employer know, and it would be appropriate for the employer to take some action in terms of awareness and their location and their practices within the childcare.

Tim:Someone has pointed out that RANZCOG recommends testing in childcare workers for CMV. Someone is asking about the resources, the poster that you use, the pamphlet for giving out information – is that available for us to use?

Bill : Yes, it is available. It is just becoming available and it is just going through the process of New South Wales Health in terms of making sure that it does not conflict with other guidelines and give a confusing message. We hope to have it available within the next sort of couple of months. It is not available right now because of those processes. It is available through the Cerebral Palsy Alliance and through the Congenital CMV Association, separate to the Ministry of Health. I guess the second thing is that we have pushing RANZCOG to have guidelines around congenital CMV and it is only the last 2-3 weeks that Lisa Hui and Antonia Shand who are obstetricians and maternal foetal medicine specialists have negotiated to have RANZCOG guidelines to include the awareness and the things that we have been discussing tonight around congenital CMV. So that is a great move forward.

Tim: Are there any particular symptoms in pregnant women, like URTI symptoms or mild viral symptoms or anything that might encourage us to test them for CMV during the pregnancy?

​Bill: Yes, again a really good question. The reality is from our experience, that the only group where I see definite congenital CMV symptoms are those who say, look I have got a toddler, I am tired all the time but one day I just could not get out of bed. So it is not the fatigue that goes with having a child and being pregnant which is, you know, substantial, but it is a very different form and they have you know, a classical presentation, very sore throat, adenopathy, fever and they have severe fatigue. I actually think the majority of women in our studies where they have said, oh look I had symptoms, if you actually question them closely, they probably had a cold or a rhinovirus, and that is the most typical misdiagnosis we get because CMV really does not cause that kind of syndrome. So the answer to your question is, that classical CMV you know, syndrome which is infectious moonlike, lots of fatigue, sore throat, glands up and a fever.

Tim: Yes. Again, someone is asking in regards to antenatal care, where they have a male patient who contracted CMV, and so he is seropositive, but the wife is seronegative, there is presumably an ongoing risk of transmission to his wife in the future if she was pregnant.

Bill: So again, good question. CMV is excreted in semen but once the primary infection is over in the male, the risk of transmission from him to his female partner is really pretty low. I guess given that 60% of males say between the age of about 35 and 45 are seropositive, and about 60% of women as well, you cannot do too much or never have babies. I think you have got to have some sense around it if the infection was say within the last couple of weeks then the man may be viremic and his risk of excretion in semen is much higher and it may be worthwhile in fact testing his blood to see whether he is still viremic. Whereas if his infection was you know, six months ago, three months ago, then the risk of transmission has got to be very low. And if it was years ago, and he is just IgG seropositive, then he is like two thirds of men who are you know, may get their partner pregnant and so it is almost normal.

TimWe have got a few people asking for clarification about people who are IgG positive, whether they, does that make them immune to CMV or does it reactivate, or do they get reinfected with CMV?

Bill:  Yes, I will try and clarify. It is slightly complex because there are a few things. A woman who is CMV seropositive is CMV immune. However, she can reactivate CMV because it is a latent virus like herpes simplex or varicella zoster, and the big difference with CMV is that it probably occurs more commonly, so in the non-pregnant women, probably once a year or a couple of times a year and in a pregnant woman, something like one in six of them will reactivate CMV. Now that does not mean one in six is going to transmit to their baby, it is just that they are immune, but they have a latent virus which from time to time reactivates and during pregnancy with the immune suppression of pregnancy, they are more likely to reactivate. We really do not have the information to say that those women are more likely to transmit, but you would think that they are. Does that mean that we should be testing all pregnant women? No, because of the issues around anxiety when we really cannot do anything about it, and thirdly around the low risk of transmission with each of those events.

Tim: Yes. And it has ticked over to 8.30, so we shall just look at the learning outcomes slide there which shows us the things we have covered tonight. You will all get the opportunity to say whether we have achieved those learning objectives, those learning outcomes, in your evaluation. I would like to thank Bill very much for that hugely informative session on congenital cytomegalovirus infection and also Sammi for running the presentation and webinar behind the scenes so effectively so we could all hear and see. I would like to wish you all a very good night. If you do have any remaining questions, Sammi will let you have the email address for that, but I hope you have all found that very useful. Thank you very much, have a good rest of the evening.

Sammi:That is great. Thanks, Tim. And just again, a big thank you to Bill and Tim and everybody on line and we hope you enjoy the rest of your evening. 

Current as at: Friday 6 September 2019
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