All right, so our last and final speaker is Natalie Bozzoie from Oshner Medical Center. So we've given her the daunting task of covering autoimmune disease as well as viral hepatitis. Yeah, so good luck. Thank you for recognizing that. Okay, thank you to the organizers and ASLD for inviting me to give this lecture. These are my disclosures. So in today's talk, I'm going to only be able to highlight a few things about hepatitis A, E, and the herpes simplex virus. I'll spend a little bit of time on hepatitis C, discussing the interaction of pregnancy and maternal hep C infection, and then discuss with you the evolving screening discussion that's going on in pregnancy and hepatitis C and what's new in treatment in the era of DAA therapies. I'll briefly review mother-to-child transmission in hepatitis B in pregnancy, and then end off reviewing a little bit of the natural history and treatment in autoimmune hepatitis. So hepatitis A is associated with preterm labor and premature rupture of membranes, but has no significant impact on maternal or fetal outcomes, and the pregnancy state itself does not alter the course of acute hepatitis A. It's important to note that vertical transmission has been reported with hepatitis A. So if you have a mother that's been diagnosed with acute hepatitis A, within two weeks of delivery, the neonate should receive hepatitis A immunoglobulin. In contrast, hepatitis E is associated with an increased risk of acute liver failure during pregnancy that carries with it a high maternal and infant mortality rate. It appears to be fairly rare in the United States, but I've mentioned it because it may be going underdiagnosed due to limited awareness of this virus in pregnancy. Hepatitis E viral lows have been found to be higher in pregnant women compared to non-pregnant women and higher in fulminant hepatic failure pregnant women compared to pregnant women with acute viral hepatitis. Hepatitis from the herpes simplex virus is very rare. It's important to note that the pathognomonic mucocutaneous lesions are present in less than 50% of cases. This makes the diagnosis extremely hard to make in pregnancy. And unfortunately, the immortality rate is very high, up to 74%. So if your suspicion is high for hepatitis from herpes simplex, it's recommended that you consider starting empiric acyclovir treatment. Hepatitis C infection appears to have little impact on pregnancy. There's a higher risk for premature rupture of membranes in association with gestational diabetes as high as a 60% increase in one study, but that high an increase was not confirmed in other studies. Pregnancy itself does not appear to negatively affect chronic hepatitis C. There are reports of ALT and viral load fluctuations, and this is likely due to the immune suppression during pregnancy and immune reconstitution that occurs after delivery, but these fluctuations remain of unclear significance. There are both reports of increases in fibrosis rate progression as well as lower rates of fibrosis progression in various studies. And unlike hepatitis B, there are no postpartum flares. It's also now been reported that the hep C infected pregnant woman has a 20-fold increase in intrahepatic cholestasis of pregnancy, and it's associated sequelae, so if you have a patient that develops this, they need to be referred to a high-risk obstetrical specialist. Hepatitis C also impacts neonatal outcomes. Reports have shown an increased risk of inter-uterine growth retardation, low birth weight, preterm delivery, and congenital anomalies. But it's important to note that these risks may be confounded by comorbid conditions such as substance abuse, and in the opioid crisis, this is becoming more of an issue. What about screening? Well, it's already been mentioned that in the United States, screening for hepatitis C is not part of routine perinatal screening, and this is likely because of the fact that overall the hepatitis C prevalence is low in pregnant women, and perinatal transmission is also relatively low. And the current ACG guidelines that came out fairly recently in liver disease and pregnancy, the current U.S. Preventive Task Force and the CDC guidelines recommend that only pregnant women with risk factors for hepatitis C should be screened. But this, I think, is slowly changing. And why is it changing? Well, hepatitis C infection present at the time of delivery increased 89% in the United States from 2009 to 2014, and this is from birth certificate data. It's attributed to the surge in injection drug use associated with the opioid crisis, and in one study, 68% of pregnant women with hepatitis C had opioid use disorder versus only 1% who were not using drugs. This slide depicts the rate of hepatitis C infection per delivery hospitalizations by opioid use disorder between 2000 and 2015. Time is along the X-axis, and the rate of hep C infection per 1,000 births along the Y-axis. The hatched line are the pregnant women without opioid use disorder, and the solid blue line are the women with opioid use disorder. And over the 15-year time span, you can see that in the women that did not have opioid use disorder, the hep C rate of infection increased from 0.7 to 2.6 per 1,000 deliveries in contrast to the women with opioid use disorder, where it increased from 87.4 to 216.9 per 1,000 births. So if we are using risk factor-based screening and we have an opioid crisis, you would think that we should be capturing all the new infections. Well, as it turns out, there's literature that risk factor-based testing in general has not been shown to be effective, and we now have reports coming out that this also holds true for hepatitis C in pregnant women. In one study, the prevalence of hepatitis C was found to be 3.18% if all the pregnant women were tested, but it dropped to 0.95% if they only tested the women, the pregnant women that admitted to having a risk factor. In addition, there are inconsistent screening and counseling practices among obstetricians and gynecologists. In one study, only 49% of OBGYNs tested for hepatitis C when they had a reported high risk factor such as intravenous drug use in their patients. So as a result of all of this, IDSA and the ASLD hepatitis C guidelines have actually published that they recommend that all pregnant women should be tested for hepatitis C infection. And I think the other thing that is now emerging, especially with the opioid crisis, the question becomes, is once enough? If you test the first time you see the patient and you have a patient that continues to use drugs, once may not be enough during pregnancy since she may be at risk of actually acquiring hepatitis C later in pregnancy. The U.S. Preventive Services Task Force is also changing its recommendations. In 2013, they added one-time testing of adults born between 45 and 65, and this year they have announced a draft recommendation to screen all persons in the United States between the ages of 18 and 79. Perinatal transmission, from a recent meta-analysis, it's estimated that the perinatal transmission rate is 5.8% in mono-infection and 10.8% in co-infection. There are various risk factors. It remains a little bit unclear as to whether viral load is truly a risk factor. Genotype appears to have no effect, HIV increases the rate, and intravenous drug use appears to be an independent risk factor. However, there's no proven perinatal strategy to date to reduce risk. We generally recommend that you avoid invasive procedures such as internal fetal monitoring and amniocentesis. Vaginal delivery does not seem to increase the risk, and thus C-section does not necessarily have to be recommended. It's important to note that prolonged rupture of membranes greater than six hours may increase the risk. Taken together, perinatal transmission, although low, is the primary cause of hepatitis C infection in children in the United States. And unfortunately, these hepatitis C exposed infants are not adequately screened. In part, this is due to missing cases from risk-based screening that I've already mentioned. And in addition, very few of these hepatitis C exposed infants have well-child visits. In one study, the rate was only 31% of these children actually having well-child visits, and of those that had the visits, only 30% were actually screened for hepatitis C. So taken together, the hepatitis C guidelines are now recommending that we consider treating women before pregnancy if it's practical and feasible to help reduce perinatal transmission. Screening, however, is still not recommended during pregnancy since we have no safety and efficacy data. And if you have a patient who becomes pregnant on these drugs, then there needs to be a discussion about the risks versus benefits of continuing treatment with the physician. So what do we know about DAA therapy during pregnancy? Not a lot. There are no large-scale clinical trials evaluating safety of DAAs in pregnancy, but my understanding is there are some clinical trials that are being planned. There are only a couple of small studies that evaluated 12 weeks of sofosbuvir and lodipasvir that reported 100% SVR12 with no obvious safety concerns, but this really only were in a handful of patients. So we really don't have a lot of data. And currently there are no data available on the use of pangenotypic regimens during pregnancy. What are the considerations of hepatitis C treatment during pregnancy? Well, one of the first ones is that we can now actually consider it because ribavirin is no longer the cornerstone of therapy. Our DAA regimens are ribavirin-free. Women are typically engaged in healthcare during pregnancy. In one study, 60% of hep C-infected women were willing to undergo treatment during pregnancy to reduce vertical transmission despite the lack of safety data. And then therapy duration is very short, 8 to 12 weeks. So some consideration about giving therapy later in pregnancy, similar to what we do to prevent and reduce perinatal transmission with hepatitis B. There are now reports of spontaneous clearance of hepatitis C in the postpartum period. One study reported up to 10% of postpartum women became hep C RNA undetectable. Another study from Egypt reported 25% rate, and this was strongly associated with the IL-28B allele. So it's now recommended that women should have their hep C RNA re-evaluated after delivery to see if they spontaneously clear. Just a quick note on breastfeeding. It is considered safe if the mother has hepatitis C and should be avoided if there are cracked nipples or skin breakdown or if there's co-infection with HIV. Hepatitis B. So all pregnant women are universally screened for hepatitis B, and the reason for this is that the risk of chronic hep B infection is linked to age of exposure. Without immunoprophylaxis, 90% in infants, 50% in toddlers, and 5% in adults. Immunoprophylaxis with hepatitis B immunoglobulin and hepatitis B vaccine has decreased perinatal transmission should be given within 12 hours of delivery. Hepatitis B is associated with failures, and the women who fail this are the women with high maternal viremia, is correlated with the highest risk for mother-to-child transmission. In a study from Australia, there was a 9% immunoprophylaxis rate in those with an HBV DNA of greater than 2 times 10 to the 7th IUs per ml. And in a recent study, the magnitude of mother-to-child transmission risk and failure of immunoprophylaxis was stratified according to viral load. A 3% risk in those with a viral load of 2 times 10 to the 5th to 1.9 times 10 to the 6th. 7% in those with 2 times 10 to the 6th to 1.9 times 10 to the 7th. And 8% a risk with greater than 2 times 10 to the 7th IUs per ml. We now have a growing body of evidence that antiviral therapy in late pregnancy actually reduces mother-to-child transmission in those at highest risk for immunoprophylaxis failure. A recent systematic review reported a significant reduction with the use of lamivudine, telbivudine or tenofovir. There are also a couple of studies looking at tenofovir itself in the third trimester and these studies showed a significant reduction in women with high viral load. So the ASLD now suggests antiviral therapy to reduce mother-to-child transmission in those with HBV DNA levels of greater than 200,000 IUs per ml. Tenofovir is preferred because of its lack of resistance and its safety profile in pregnancy. TAF has not yet been studied and is generally recommended to start therapy at 28 to 32 weeks of gestation. Similar to hepatitis C, breastfeeding is safe in hepatitis B unless you have cracked or bleeding nipples. The antiviral drug labels to date do not recommend breastfeeding when taking these drugs, but there's a growing body of literature that supports their safety during breastfeeding. Now moving on to autoimmune hepatitis. There are no systematic reviews or meta-analysis on the management of autoimmune hepatitis during pregnancy. I think an overall goal is optimal control of autoimmune hepatitis before, during and in the postpartum period. The most challenging issue remains the medications that we choose to use in autoimmune hepatitis. An overall key principle, I think, is that a healthy mother has the best chance of a pregnancy with optimal fetal and maternal outcomes. Natural history. It's important to note that some women will have their initial presentation of autoimmune hepatitis during pregnancy, so be aware of that. And there are both intrapartum and postpartum flare risks. The highest risk is probably postpartum with reports of rates between 30 and 50 percent. And autoimmune hepatitis is associated with an increased risk of fetal prematurity and loss with worse outcomes with poor disease control, especially in the absence of or discontinuation of treatment before or during pregnancy. I'm going to share with you the largest series, which comes from King's College, and we're honored to have a physician from King's College here who knows a lot more about this than me. In this series, 81 pregnancies in 53 women, at conception, 75 percent were on therapy. Of the ones on therapy, 74 percent had been stable on medications for greater than a year prior to conception, and 25 percent were not on treatment prior to conception. Two had de novo autoimmune hepatitis. Five had cirrhosis and were not on medications. Six were in remission and discontinued medications. And seven stopped to become pregnant. Pregnancy on therapy versus not on therapy in this series showed no differences in live birth termination or miscarriage rates and no differences in gestational period. But there was a difference in the incidence of flare. Fifty percent flare rate not on therapy and 26 percent if they were on therapy. And the flare was more likely if no disease remission for greater than one year prior to conception, 48 percent versus 23 percent. What about treatment in autoimmune hepatitis? Well, the ASLD practice guidelines from 2010, a number of years ago, recommended pregnancy zone monotherapy in pregnancy, but we now have a growing body of literature using corticosteroids and or azathioprine in pregnancy. We have no data for the use of budesonide in pregnancy, and as already mentioned in an earlier talk, cell septus contraindicated due to teratogenicity. Our largest experience in pregnancy comes from the inflammatory bowel disease literature. Azathioprine use had been studied systematically in 3,000 azathioprine exposed pregnancies and was associated with an increase in preterm births, but importantly, no increase in congenital anomalies or low birth weights. So overall, we have amounting evidence for the safety of azathioprine in pregnancy, and I think a growing concept is this need for disease control that outweighs any potential small risk of treatment-associated adverse events. So my key takeaway points for hepatitis C, we are moving towards screening all pregnant patients, which I think is long overdue. It's important to remember that perinatal transmission is the primary cause of hepatitis C infection in children, and remember that spontaneous clearance of hepatitis C occurs postpartum and requires reevaluation of the infection after delivery. Hepatitis B, we have a lot of data now that antiviral therapy in late pregnancy reduces maternal... reduces perinatal transmission. And in autoimmune hepatitis, the goal is optimal control of autoimmune hepatitis before, during, and after pregnancy, and this need for disease control outweighs the potential small risk of treatment side effects. Thank you. Okay, well, we have some time for a few questions, if there's anybody who wants to come to the podium. Yes. Jose, Nijmegen, Netherlands. Could you tell me what you do in clinical practice if a female with autoimmune hepatitis has had a child? How frequently you let patients come back to the outpatient clinic to check for ALT levels? I didn't quite hear the beginning of the question. Could you repeat it? A patient with autoimmune hepatitis... Yes, autoimmune. ...has delivered a child, what happens in your clinic? Generally speaking, we try to have the patient, when I see them the last time during pregnancy, I will arrange for them to have labs at one, three, and six months postpartum. And I also try to communicate with their OBGYN to remind them that when they see them, because they generally will often see them before they see me, to make sure that that happens. And then I have my staff call them if I don't see those particular labs. You have good staff. One more question. Okay. To the back mic. One more question. Go ahead. Question. Hepatitis B in pregnancy. So should you start an off of it week 38 or week 32? When do you stop it postpartum? It's a great question. I didn't cover that. So there is some data now that you can stop pretty much at delivery. And a lot of people want to do that in order to avoid using the drugs for breastfeeding. And there generally haven't been any increase. The concern always was a flare would occur if you did that. But stopping at delivery and waiting the three months has been shown not to really make a difference. I would recommend that you monitor just in case it happens. But I feel pretty comfortable about stopping at delivery now.

autoimmune diseases

viral hepatitis

pregnancy outcomes

hepatitis A

hepatitis E

hepatitis C