OK, I think. I'm ending uh the scheduled presentations. Thank you, Doctor Najra Nagaraj. That was fascinating, and I definitely understood some of it. Um, so my name is Kara Markham. I'm one of the maternal fetal medicine specialists at the University of Cincinnati and at Cincinnati Fetal uh Cincinnati Children's Fetal Center. Um, as one of the co-presenters slash moderators, I want to thank myself for inviting myself to present today. It was a really good choice. Uh, despite that intimate relationship, I somehow missed the memo that my talk was supposed to be a little longer than last week. So, um, start thinking of some questions because we're probably gonna have a good amount of time to field those at the end, both, uh, with my talk and the one before. Um, but I am focusing on CMV and pregnancy, specifically to treat or not to treat. Um, as many of you know, the topic of cytomegalovirus in pregnancy is actually more complicated than it, it can seem at first blush, and there are a lot of different facets of the disease that, that one can talk about. Um, including maternal to child transmission rates, um, uh, diagnosis, you know, involving things such as serologies and IgG avidity and amniocentesis. And for the sake of time, I'm, I'm not gonna go down those rabbit holes. I'm mostly gonna focus on showing some of the, uh, representative kind of rapid-fire, um, example of ultrasound and MRI images that may be seen. in infected babies, but mostly I'm going to focus on whether or not treatment makes a difference. And that has kind of more implications than just for the fetus at hand because there's a lot of discussion, um, at least in the United States, about whether or not to screen mothers for CMV, uh, whether they've been infected in the past, they have immunity, whatever it may be, and the argument against that has always been, well, we don't necessarily have anything to Um, treat these babies with even if they are infected. But if we ultimately decide that we do have a good treatment option, then screening may become more common. I have, um, I have a relationship, consulting relationship with Johnson and Johnson, uh, for other research studies, but that is not applicable to this study, so I have no relevant disclosures, and my outline is included here. So briefly, why do we care about congenital CMV? Well, it's the most common congenital viral infection in neonates. It occurs in about 30,000 children annually. And of those babies that are congenitally infected, about 1 in 5 will experience long-term health sequelae. Um, now, we're focusing a lot on, solely, I would say, on the babies in which we have suspicion for, um, congenital infection during pregnancy, but importantly, um, most of the cases, there's not that suspicion. So, uh, for most of these congenital cases, they occur in the absence of suspicion for maternal infection, which again brings up whether or not more robust, um, screening in a broader, uh, broader Capacity would be helpful if we have an available treatment. Long-term sequelae primarily involve the uh central nervous system. Infected, affected individuals display hearing loss, varying degrees of that. They can have different ophthalmologic disease, can have seizures, hypotonia, encephalitis or encephalopathy, hydrocephalus, and intellectual disability. And these sequelae tend to vary depending on whether or not the neonate is symptomatic at birth. And that's kind of a common You know, discussion point here is that we do sort of in our minds, separate these babies from whether or not they're symptomatic at birth to whether or not they're asymptomatic at birth. Um, but those who are symptomatic tend to have anatomic disturbances, and to some degrees, those are gonna be the ones that were more able to identify abnormalities prenatally, while those who are asymptomatic tends to have, tend to have more functional, um, abnormalities such as intellectual disability. Less than 25% of infected fetuses will have abnormal ultrasound findings. Um, but I've listed here the possible findings that can be seen with ultrasound or MRI. Importantly, the presence or absence of imaging findings can assist us with counseling. Um, for example, there was a study by Guerra etal that showed that 78% of fetuses with ultrasound findings were symptomatic at birth compared to 52% of fetuses without ultrasound findings. So, according to this, the negative predictive value of ultrasound, at least for symptoms at birth, although not necessarily for long-term sequelae, uh, is about 50%. Um, so we'll go through some kind of rapid-fire examples of imaging. I think many of you will be familiar with many of these. So, uh, the first one is a look at the fetal abdomen, specifically, um, highlighting ecogenic bowel. This needs to be bowel that is as bright as bone as depicted in this area and this area. This is an example of epigenic adrenal glands. This one's, I think, very striking. So we can see normal um adrenal glands here, and then you can see very bright adrenal glands in the slide to the left. The next image displays um increased echogenicity of the tissue surrounding the ventricles, um, and also, um, I see some suspicion that there could be hemorrhage, um, in one area of that, um, lateral ventricle, the one towards the down part of the fetal skull. Um, and I suspect many of you are familiar with one of the most common findings that we talk about, which is ventriculomegaly. Um, and in fact, it's so common that I included a second slide with two more images, mostly because it's really easy for me to find images of ventriculomegaly. Um, in this next image, if you focus in on the biometric measurements, those are included for a reason. You can see that the head circumference and biparietal diameter are both at less than the 2, at 2.5th percentile or so findings that raise concern for microcephaly. And the parenchyma also appears abnormal to me in this image, a finding that may be better assessed via MRI. And finally, this last ultrasound image shows the placenta. Usually, when we talk about fetal infections, we talk about whether or not the, uh, we have placenomegaly, um, edematous placenta, like you can see with syphilis, for example. In this case, I'm seeing a lot of increased echogenicity, a lot of little foci of increased echogenicity, which probably indicates placental infection with CMV. And of course, other findings are common on ultrasound, um, including fetal growth restriction, fluid abnormalities, most commonly oligohydramnios, and we can see hydrops fetalis. So what about MRI? Um, well, MRI doesn't seem to be super helpful when the ultrasound is normal. Um, it can be helpful. I mean, one study demonstrated that about 6% of fetuses with a normal appearing ultrasound will have additional findings or I should say abnormalities at all identified on MRI. But it's more helpful in the setting of ultrasound abnormalities. Uh, that's Same study showed that 50% of fetuses with extra cerebral abnormalities, things like echogenic bowel, were found to have intracranial abnormalities when evaluated on MRI. So MRI certainly serves, uh, a potential role when evaluating these fetuses, um, evaluating these fetuses and counseling the mothers about the possible sequelae. I'm far more comfortable interpreting ultrasounds, so I didn't include a lot of MRI images, but I did include a few. Um, and luckily, my handy dandy radiologist provided the lovely arrow signs to help us. Um, so this first example is an example of splenomegaly. The next one is hepatomegaly, and even I can see that one. I mean, we can see the, um, liver extending from the diaphragm all the way down to basically the pubic bone. That's a very large liver for this baby. Um, and also in this image, if you look at the brain, you can definitely see suspicion for ventriculomegaly and probably also for some increased, um, uh, extrapriable fluid surrounding the brain as a whole. The next image shows polymicrogyrhea, which is a num another possible finding that can be seen with um CMV. So, we, uh, now we're, you know, we've rapid-fire gone through some of the images, but, you know, what does all this mean for, for the baby? And there are a lot of different numbers that can be thrown around when talking about, um, CMV in pregnancy. For example, with primary maternal infection, there's about a 40% chance of maternal to child transmission. If it's recurrent, it's about 1% roughly. However, because recurrent infection is so much more common than Um, primary infection, most cases, congenital infection will be in recurrent, um, maternal infections. But again, we also talk a lot about symptomatic versus asymptomatic at birth. And in the setting of fetal infection, about 85 to 90% of babies will be asymptomatic at birth, 15 to 25% of whom will exhibit sequelae later in life. 10 to 15% of these babies will be symptomatic at birth, uh, with about a 5% risk of death, and a 50 to 65% risk of serious long-term neurologic swelling. So obviously the question then becomes, Is there any treatment that can improve these outcomes? And again, when we talk about treatment and whether or not it can improve outcomes, we talk about, really, I would say two primary groups. The first is when we have evidence of maternal infection, and we're talking about whether or not treatment prevents maternal to child transmission. So with those studies or those results, you'll hear us talk a lot about whether or not the amniocentesis is positive. And then the second group is when we have confirmed or highly suspected fetal infection, can we improve outcomes for the baby, um, with treatment? We usually use whether or not the baby is symptomatic at birth as a marker for whether or not this treatment has played a role. Although a more accurate question would be whether or not the child has long-term sequelae from the infection. It's just, of course, that studies become harder when you're talking about more long-term evaluation. Um, my understanding, not a neonatologist, but is that gancyclovir is the gold standard for neonates with congenital CMV. Uh, it's mostly been shown to improve or stabilize hearing, but use can be limited by side effects and, uh, significant morbidity. But what about earlier treatment? Maybe by the time we have a baby that's symptomatic at birth, um, it's too late to make much of a difference. Um, maybe if we delay treatment until after the baby is born, the horse is already ahead of the cart or whatever your favorite saying is. Uh, maybe we can make more of a difference by treating the mother in an effort to benefit the baby. Well, as recently as 5 to 10 years ago, we had a lot of hope that CMV-specific hyperimmune globulin would be a super useful tool. And for the sake of my mouth being able to say all these words, I'm just gonna call this IVIG. So this was based on a study that showed an adjusted odds ratio in rates of congenital infection of 0.02 when IVIG was given for treatment, meaning those with converged CMV presence in amniotic fluid. And an adjusted odds ratio of 0.32 when it was given for prevention, meaning moms with a recent primary infection. But the study, although we kind of jumped all over it and said, OK, well, this is it, we've, we've, we have the answer, um, it wasn't a randomized control trial, and subsequent better designed studies failed to replicate the success. So, for example, Uh, an RCT by Ravello et al demonstrated no significant difference in rates of congenital infection with IVIG compared to placebo. However, the sample size would have needed to be 3 times higher to detect a 14% difference in the uh primary outcome with that trial. A subsequent RCT was performed by Hughes and colleagues through the maternal Fetal Medicine Units Network as part of the CDC. This, uh, was a big study. I was actually involved in it when I was at Ohio State. Um, it involves screening women for CMV serologies at less than 23 weeks. If the baby had evidence of infection, they were excluded, but if the mother was positive without ultrasound abnormalities, they were approached to enroll in a randomized control trial. Um, of IVIG versus placebo. 712 women were found to have primary CMV infection, which was far less than what we thought was going to be, um, and about just short of 400 patients were enrolled in the randomized control trial. The study was terminated early after the 5th interim analysis because it did not meet preset conditional power cutoff. And the primary outcome was a composite. It was confirmed fetal infection, congenital infection diagnosed by 3 weeks of life, or a fetal or neonatal death. 22% Almost 23% of participants met this primary outcome in the IVIG group compared to 19.4% in the placebo group, a finding that was not clinically significant. And a follow-up manuscript was published in 2023 reporting outcomes at two years of life. Uh, this likewise failed to show an improvement in hearing or developmental in, um, outcomes. So, after the publication of these RCTs, attention kind of turned away from IBIG really is not recommended outside of a research protocol at this point in time. We've sort of focused a little bit more though on the possibility of antiviral drugs, um, such as vacyclovir. And the data for this may be a little bit more encouraging. So we'll first talk about some of the data regarding prevention of vertical transmission, um, specifically in the setting of maternal CMV infection, and then we'll talk about, um, use in, uh, the setting of infection. With the goal of improving outcomes for the infected fetuses. So with this first consideration, um, the caveat to all of this is that these studies were done in the setting of primary, not recurrent maternal infection. And as mentioned earlier, most cases of congenital CMV are actually with recurrent maternal infections. We're missing out on a large subset of patients who could potentially benefit from treatment. A randomized controlled trial by Shahar Nissan showed decreased rates of CMP CMV positivity on amniocentesis with vacyclovir following maternal infection either near the time of conception or in the first trimester, a finding that in that study was largely driven by treatment effects following exposure in the first trimester, uh, possibly due to the fact that, uh, treatment was initiated earlier in relation to the maternal infection in the, in those patients. Um, it also demonstrated lower odds of CMV related morbidity for the baby with vacyclovir use. A meta-analysis that included 3 RCTs or what they call quasi-randomized studies, including the one by Shahar Nissan, showed an adjusted odds ratio of 0.3 with vacycloviric use for positive amniocentesis, a finding that was seen both with peri-conceptual, conceptualual maternal infection and infection in the first trimester. They also demonstrated decreases in rates of termination of pregnancy due to severe fetal findings and in rates of neonatal infection. Again, the gestational age initiation of treatment had a positive correlation with outcomes, and they showed a number needed to treat to prevent one positive amniocentesis of 6.9. What about treatment to improve the outcome of infected fetuses? Uh, a meta-analysis, meta-analysis by D'Antonio and colleagues included 8 studies and showed an increased likelihood of asymptomatic infection in the neonate with treatment as compared to no treatment, with a pooled adjusted odds ratio of 2.98. There was no difference in the risk of perinatal death, termination of pregnancy, or anomalies identified in, on ultrasound, nor was there a difference in CMV-related morbidities such as perinatal death, neurologic symptoms, or hearing symptoms. A study by uh Lorez and colleagues, I apologize if I mispronounced that name, suggested promising effects in the subset of infected fetuses with ultrasound or other imaging abnormalities. They specifically excluded fetuses with severe brain uh brain abnormalities, but they included, um, fetuses with what they described as non-severe cerebral abnormalities. And they showed that the proportion of asymptomatic neonates increased from 43% without treatment to 82% with treatment. And they showed that these asymptomatic neonates remained asymptomatic at 12 months of life. So that's kind of a rapid-fire review of some of the available literature. Um, And quite frankly, many experts now recommend acyclovir. Specifically, a dose of 8 g per day in women with CMV infections in pregnancy, which is a pretty big dose. Um, appropriate counseling is obviously needed, including a discussion of the adverse effects of treatment itself upon maternal health. Um, these effects are reported in about 2 to 3% of exposed women. It can include relatively minor things such as headache, but it can also include things like reversible kidney failure. That being said, I can't help but wonder if we're introducing this before it's really ready for prime time. We often, like we did with IVIG, fall into a trap of just wanting to do something. It's so hard to see these fetuses with sequelae, to have this suspicion for infection, and to say, well, there's nothing I can do to help. you, we'll see what the baby looks like when, when the baby is born. It's hard to not treat. There's, um, psychological benefits both for physicians, providers, and for um family with treatment as opposed to non-treatment. So, um, can't help but wonder if we're falling into that trap with alcyclovir. Now, it's not as Bad of a trap, I guess, since the side effects um are not as severe as they can be with IVIG, but I still think that we're due for a good RCT to really settle this, this issue, um, and, and really get more information. Now, of course, a good defense is our best offense, so we should always encourage good hygiene like hand washing and um for those of us who aren't fortunate to live in a country like the US, uh, filtering water or not drinking from mud puddles, that sort of thing, um, and perhaps someday, that long-awaited vaccine will be ready for prime time and um we can really improve outcomes just by not letting our patients get infected during pregnancy. So, um, that concludes the formal part of the webinar. Thank you again.
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