Cytomegalovirus in pregnancy: prevention, maternal screening, and the role of antivirals

[Music] Welcome to the Australian Prescriber podcast. An independent, no-nonsense podcast for busy health professionals.

I'm Dhineli Perera, your host for this episode, and I'm really delighted today to be chatting to Professor Lisa Hui about this incredibly important and evolving issue of cytomegalovirus known as CMV in pregnancy. Lisa is a maternal–fetal medicine specialist at the Mercy Hospital for Women in Melbourne and professor from the Department of Obstetrics, Gynaecology and Newborn Health at University of Melbourne.

Together with her team, Lisa shines a really critical light on the importance of understanding the role of prevention, screening, and antivirals within the sphere of CMV in pregnancy. A really warm welcome to you, Lisa.

Thank you for having me on the podcast.

So Lisa, I thought you could start us off by briefly describing what CMV is and how it is transmitted.

CMV is a very common virus and it actually belongs to the family of herpes viruses that we all know and love. And like other herpes viruses, once you catch it, it stays in your body for life like the cold sore virus or varicella or the chickenpox virus. And in healthy adults, usually we might not have any symptoms or just very mild symptoms.

And by the time we're adults, the majority of people in Australia have actually acquired this virus. Having said that, although it doesn't cause issues for healthy people with intact immune systems, there are certain situations where it can cause problems, and that's if someone's immunosuppressed or if a pregnant woman catches it in early pregnancy because it can then pass across the placenta to the developing baby.

And so when we talk about women in pregnancy, where do they typically get it from or acquire it from that you see as being a risk for this group?

CMV is a human virus, so it's spread from person to person. And the most common source of infection are actually their toddlers. So we all know that young children, they're always picking up viruses from each other at daycare or playgroup and bringing it home and spreading it amongst the family. And unfortunately, CMV can be one of those viruses that they bring home with us. And toddlers are thought to be the most common source of the infection because they shed this virus in large amounts and for a very long period of time.

Okay. So then if children under the age of 5 are this major reservoir of CMV, are all pregnant women caring for this age group, including childcare workers potentially, are they really at risk?

Yes. So they're the group that we really would like to reach in terms of our public health message and providing them with information about how to reduce their risk of acquiring this virus during pregnancy. So for many years, we've been saying that all women in early pregnancy and those planning pregnancy should be given education about CMV and how it's transmitted in ways of protecting themselves. This is an opportunity for us to get that message out to those women at higher risk.

So that's women who have young children at home or childcare workers who look after preschool-aged children. And because this virus is shed in body fluids, the sorts of hygiene precautions that have been shown to reduce the risk of acquiring this infection include hand hygiene after changing nappies or wiping a toddler's runny nose, not kissing children on the lips, kissing them on the top of their head instead.

You really want to avoid getting their saliva into your mouth. And then the other health behaviour that we're encouraging women to try and remember is not to eat food that has been in their child's mouth and not to share eating utensils, toothbrushes and that sort of thing. So it really is behaviours around reducing exposure to young children's saliva and urine.

Yeah. And in this post-COVID era, that's probably something that we've all kind of adjusted to, right? Although people lax, and especially with your own child, you do tend to just treat... they're an extension of your own body. And so therefore you can share all these things without risk, but remembering that when you are pregnant is critical, right?

Yes. And I think in the past, some healthcare practitioners have been a little bit ambivalent about getting this health message across because we are asking women to change their behaviour and how they interact with their young children. And we know that people can't be 100% perfect all of the time. Of course, there are going to be times when your toddler comes up to you, gives you a big sloppy kiss on the mouth.

We're not saying that people need to be able to adhere to these precautions 100% of the time. But when I talk to women who've been affected by CMV in pregnancy, they're very adamant that this information should be out there. We shouldn't be withholding it from people because we don't want to create anxiety or we think it's not our place to tell people how to behave with their own children.

We have also done a survey of pregnant women and given them these hygiene messages. And they've all said they think it's really important for women to know, even though it might make them feel slightly anxious, they do want to know how to reduce their risk of acquiring this infection.

Absolutely.

Yeah. A lot of women say that they know all about toxoplasmosis and not touching kitty litter, or they're told not to eat soft cheeses to reduce their chance of catching listeria, but actually CMV is much more common than either of those 2 infections. And really, I think if we're going to take the time to talk about soft cheeses and kitty litter, we should be talking about hand hygiene and reducing our chance of catching this virus from toddlers.

Absolutely. When you think about the ramifications of it and what it could help prevent, I can understand why a lot of your patients are adamant that that information should be out there. How effective are these risk reduction behaviours in reducing transmission?

So giving women this information about how to reduce their risk of acquiring this infection has been shown to reduce the risk of infection in pregnancy from 7.6% to 1.6% amongst women who have a higher exposure to young children. So this was a study that was conducted in people with young children or childcare workers who have been shown never to have acquired this infection before compared to a group of women who didn't receive this hygiene information. So it definitely reduces the chance of acquiring this infection in that crucial first trimester of pregnancy.

Well, that makes it worthwhile immediately then, right?

Yeah.

So then what is the incidence of congenital CMV? And what are the potential consequences for an infant who acquires the virus via this vertical transmission? Why are we emphasising the importance of this?

Well, congenital CMV affects about one in 200 infants born in high-income countries. So the birth prevalence does vary depending on whether you're in a high- or a low-income country. It's actually higher in low-income countries, but if we're talking about the Australian context, it is about one in 200 births.

So it's a lot higher than people think. Most of these infected infants are completely asymptomatic at birth and don't have any long-term health effects, but we do know that about 10 to 15% of babies born with this infection will develop long-term sequelae, such as hearing loss, cerebral palsy, and occasionally more serious conditions like intellectual disability and epilepsy.

Okay, 10 to 15%. That's larger than what I would've thought, especially for something that in my own experience, I definitely wasn't given much education about this and my own kids are only 7 and 9. Super interesting that it's such a high percentage of infants.

Yes. So if we go on the estimates of one in 200 live births, and of them, 10% will have some sort of long-term impact from the infection, that does translate to one in 2000 babies. It's not very common, but because it's completely preventable, it really is something that I think we should be doing more about.

There was a study done of Australian children with cerebral palsy, and it was found that 8% of those children had evidence of CMV at birth when they went back and tested their newborn screening blood spot samples. So that makes it the single most preventable cause of cerebral palsy.

Yeah. Wow. Moving on to your article itself, Lisa, it describes how the risk varies greatly between primary and non-primary maternal infection. Could you please, first of all, briefly explain to listeners what the difference is between these and then why the variance between it also occurs?

Primary infection refers to when a person's been infected with this virus for the very first time. So this is an infection in a person who has no pre-existing antibodies to CMV. Non-primary infection refers to when a person catches CMV for the second or third or subsequent time. So just like COVID, you can catch CMV more than once. If someone's got antibodies already, but they have evidence of another infection, that could be either a new infection that they've acquired, or it could be reactivation of their latent virus.

So in that way, it is a bit like the cold sore virus. You can catch that once, it stays in your body for life and it can be reactivated periodically. So that's why this is quite a tricky virus to combat because it does stay in our body for life. We don't have a way really of detecting non-primary infection with our current blood tests. And the reason why our focus is on primary infection in pregnancy is because that situation poses the highest risk of the infection passing across the placenta to the baby.

So women who acquire CMV for the very first time in first trimester, their chance of the infection passing across to the baby is about 37%, and this rises to 66% in the third trimester. But although the risk of infection is higher in the third trimester, the risk of complications to the baby is much lower in later pregnancy. So that's why we really focus on the first trimester because that's the period in which the risk of complications to the baby is the highest.

Okay. The groups that are really at risk are the women that have toddlers that are looking after young children and haven't had the CMV infection before, and so their risk of acquiring it in that first trimester, they're the really high-risk group.

Yeah, that's right. And I think that also helps people understand how vigilant they might have to be about their hygiene precautions. It's really in that first trimester when people really should be paying most attention to that. Even though infection is possible later in pregnancy, the chance of it causing any harm to the baby is very, very low. So that's why that first trimester, when the brain's just developing and most vulnerable to the infection is where we need to focus our attention.

Moving on to screening, Lisa, can you tell us why this is so controversial? What has changed to reignite interest in this tool?

Yeah. So at the moment, there is a way of testing women to see if they've had the virus before. That's just with CMV serology, looking for the presence of antibodies. And we haven't been testing all women for this before because we haven't really had a treatment or any strategy that we can offer to help deal with any infection that we detect in pregnancy. So historically, we've just relied on providing hygiene prevention advice and not try to test all women to look for infection.

However, there is an argument for testing women at a high risk of CMV infection, that is those with close contact with young children, just so that they know whether they're at risk of a primary infection, and that will help really focus the hygiene precaution messages to those who will benefit from it the most.

There's also another argument for screening or repeat testing in pregnancy now. So if we do testing at the very first antenatal visit and diagnose someone as never having been exposed to this infection before, then there's an argument for testing them again at the end of first trimester to pick up any asymptomatic infections. So this is where new data on the use of antivirals has really reignited this debate about screening and the role of repeat testing in first trimester.

So if we do a repeat test and we see that someone's gone from CMV IgG negative to positive, that means that they've acquired the infection in the first trimester. And in the past, we didn't really have anything to offer these women in terms of a treatment, but there's been emerging data over the last 5 years showing that if we give these women high-dose antiviral therapy, it can actually reduce the chance of the virus passing across to the baby. So that's where the interest has arisen in screening in first trimester. And there are several European countries that are now trialling this approach to universal screening in first trimester.

Right. So that they can do that retest and then go from there.

Yes.

So in Australia, based on the Australian Pregnancy Care Guidelines, what criteria does a pregnant woman have to meet to be considered at risk and therefore offered the CMV serology screening?

The Pregnancy Care Guidelines recommend that women with substantial exposure to young children, particularly those under the age of 5, such as childcare workers and people with young children in the home, should be offered CMV serology at their first pregnancy visit.

Okay. So it's just as simple as what we were discussing before. So really, those main risk groups.

Yep. But our Australian Pregnancy Care Guidelines don't address the question about whether we should be testing again at the end of first trimester in those women if they're seronegative at that first test. So they've really not addressed that whole question about screening to detect early infections so that we can offer antiviral therapy.

And I think it's really because we need more Australian data on the acceptability and feasibility of implementing this in a safe and consistent manner so that we don't cause more harm than good by indiscriminate testing.

Yeah. So I guess it's something that could change as more evidence comes out with the use of the antivirals, especially if we're seeing this used more broadly in the European setting, there might be more data that comes out supporting the use of those 2 tests, as well as the valaciclovir that could help and change the guidelines as time goes on.

Yes. And I think the challenge with CMV serology is that it's not always easy to interpret. So sometimes we get results where we're not really able to determine the timing of the infection. So we would offer antiviral therapy if we could be sure that the infection was in first trimester, but we often get results that don't help us with working out the timing and we do get false positive results. So we don't have a perfect test and that's where a lot of the caution is in not using a test that might cause more confusion than clarity.

I do really love Table 2 in your article, which neatly explains the interpretation of the CMV screening parameters. I find this stuff really tricky sometimes when the results come out. I'm like, 'I don't really know what to make of it.' So what would you say, looking at this Table 2 from your paper, what are the most important factors that differentiate IgG and IgM antibodies, as well as the IgG avidity when you're talking about CMV?

CMV IgG tells us about whether someone's had exposure to the virus in the past or not. This generally stays positive for life if someone's been exposed. So this IgM tells us whether the infection is likely to have been recent, so within the past 3 months.

But what we need to do if someone is both IgG and IgM positive is do a follow-up test called IgG avidity, and that tells us how mature the person's IgG is, and that's what gives us a indication of whether the infection's been within the last 3 months, whether it's been more than 3 months ago or somewhere indeterminate in the middle.

That's a great little summary of it. Thank you. And so you mentioned that some people have no signs or symptoms of CMV, can be completely silent. If they were to be symptomatic, what are the signs and symptoms of maternal CMV infection?

Well, the symptoms are quite nonspecific, which makes it a little bit hard to know when to test. But in general, the symptoms that should prompt testing include fever, lymphadenopathy, and a flu-like illness.

So not just a sniffly nose or a cough or a cold, but something very much like a flu with myalgia and swollen lymph nodes and a fever. Some of the laboratory features that might prompt testing include atypical lymphocytosis, or if someone has low platelets or abnormal LFTs [liver function tests], or less commonly, a haemolytic anaemia. CMV can cause all of those things.

So we've touched on the use of antivirals, but could you talk us through a little bit about the landmark study that you've mentioned in the article? Because I suspect quite a few listeners, including myself, may not know as much about the off-label use of valaciclovir in this space.

Yeah, sure. So in 2020, a group in Israel conducted a double-blinded randomised controlled trial, so the highest quality evidence we can get on an intervention. And in that study, they offered high-dose valaciclovir to women who had serological evidence of primary CMV infection, either in first trimester or in the periconception period, so in the 4 weeks up until their last menstrual period.

And they found that valaciclovir, given orally 8 g a day from the time of diagnosis through to about 21 weeks gestation, reduced the risk of fetal transmission from 48% to 11%. So that's really quite a big treatment effect, and it really gave us the first evidence of an effective treatment to reduce the risk of fetal infection after maternal infection.

Wow, that's a huge drop.

Yes. So they did find that there was only significant improvement in the group that had first trimester infection, and it wasn't found to be significant for those with the periconception infection. So in the 4 weeks prior to their last menstrual period.

It's limited, but still useful.

It's not without its risks though, and that's a message we wanted to bring out in this article as well. There is about a 2% risk of renal impairment in a woman. This is quite high-dose medication that's 16 tablets a day, which they'll be taking from the time that the infection's diagnosed through to about 20 weeks gestation when we would typically be recommending an amniocentesis, and then the medication's usually stopped after the amnio result.

So I wanted to ask you about that. What's the role of amniocentesis in this monitoring schedule?

So the amniocentesis is a way of detecting whether the virus has passed across to the baby or not. So it tells us whether the treatment's been successful or not. In the randomised controlled trial, they stopped the antiviral medication after the amniocentesis. So if the amniocentesis was negative for CMV, that was considered a success and the antiviral therapy was stopped.

If it came back CMV positive, showing that the virus had crossed across the placenta to the baby, then treatment was considered to be unsuccessful and it was also stopped because there's no evidence to suggest that it's beneficial to continue the antiviral therapy after a positive amniocentesis result.

Right. That's beyond the scope of this paper, but I guess there's a whole new decision that has to be made and genetic counselling that has to be done at that point if it's been shown to have been transmitted, because it's still tricky when it's not 100% of cases that end up having the significant impacts that you discussed earlier.

Yes, that's right. So it's still uncertain what the role of valaciclovir is in the case of a fetal infection.

Yeah. Okay. One last question from me. I can imagine that this can be a really stressful period for pregnant women who quite possibly didn't even know about this virus until they were well into their first trimester. Which resources have you found to be particularly useful for both the pregnant woman as well as the clinician, perhaps their GP [general practitioner] or their primary prescriber?

Yeah, there are certainly good resources out there for patient information. So the Cerebral Palsy Alliance have created a webpage called the CMV Resource Hub, and that's got downloadable pamphlets. It's got some great patient education videos on there. It's got flyers for practitioners to have in their practice, posters and pamphlets in different languages about CMV and how to reduce your risk of catching this virus.

Our patients also get a lot of benefit from reaching out to other families in the same situation. So the CMV Association of Australia is a patient support group. So again, they have a website and a closed parent Facebook page for parents and expectant parents who want to reach out to other people about this condition.

That's great. So this is in Box 2. All of the resources are there with links as well. So I'd highly recommend checking it out if this is an area of interest for yourself or for your patients or people that you know that are in this situation. I honestly have so many more questions to ask, but that's really unfortunately all we've got time for. Thank you so much for joining us today, Lisa.

Thank you very much for having me on the show.

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Professor Lisa Hui's article, 'Cytomegalovirus in pregnancy: prevention, maternal screening, and the role of antivirals', is available on the Australian Prescriber website. The views of the hosts and guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines.

Professor Lisa has received a research fellowship from Norman Beischer Medical Research Foundation for congenital CMV related studies and developed patient information brochures for the Cerebral Palsy Alliance and UpToDate. She was paid for her work to edit the UpToDate chapter on the same topic. She has also received funding for conferences associated costs as an invited speaker for multiple international conferences. I'm Dhineli Perera, and thanks for joining us on the Australian Prescriber podcast.

A reminder you can claim CPD for Australian Prescriber articles and podcasts by self-reporting through your college or institution. For RACGP members, these are fully accredited — visit our website for details.