Managing Acute and Chronic Viral Hepatitis During Pregnancy
Chronic viral hepatitis does not adversely affect the course of pregnancy, but it carries the risk of vertical transmission of the virus. Overall, chronic viral hepatitis is the most frequent pre-existing liver disease and they need to be followed through the whole period of pregnancy and overall after delivery.
HBV is an important global health problem, because of high risk of perinatal viral transmission. Before the adoption of HBIG, approximately 70–90% of infants born to HBeAg-positive mothers may became chronically infected by HBV. HBV infection does not significantly modify the clinical course of pregnancy either fertility or conception unless the woman has liver cirrhosis or liver failure. Moreover, chronic HBV infection does not increase maternal or foetal morbidity and mortality, although a recent study has shown an increased risk of diabetes mellitus, ante-partum haemorrhages and life-threatening preterm labour. On the other hand, in the presence of cirrhosis, the risk to develop significant perinatal complications and poor pregnancy outcome is higher. Moreover, cirrhotic pregnant women have usually higher spontaneous rates of maternal complications such as placental abruption, gestational hypertension and peripartum haemorrhages. By the contrary, pregnancy does not influence the course of chronic HBV infection and usually it is not considered as a possible worsening factor.
Nowadays, the risk of perinatal transmission, which represents in many areas of the world the primary source of persistence of HBV chronic infection, has focused the attention to the management of HBV infection during pregnancy. The risk is very high in HBeAg-positive patients with high viral load, but conflicting data exist about the potential role of different HBV genotypes in influencing transmission.
Among maternal risk factors affecting vertical or perinatal transmission, we also mention placental diseases or complications appearing during labour and breastfeeding, which is another major source of infection.
Together with the immunoprophylaxis, the choice of correct antiviral therapy plays a major role in chronic HBV-infected women. Not all available drugs for treatment of chronic HBV infection can be used during pregnancy, and they have an important role to avoid an exacerbation of disease that can occur in case of drug discontinuation, especially soon after the delivery, with high risk of occurrence of fulminant hepatitis causing a life-threatening condition both for mother and foetus.
Drugs used for the treatment of chronic hepatitis B (CHB) include recombinant interferon (IFN), pegylated interferon (PEG-IFN) and Nucleos(t)ides analogues (NAs). NAs are classified as nucleosides (lamivudine, telbivudine, emtricitabine and entecavir) or nucleotides (adefovir and tenofovir). All these drugs have been approved in Europe for CHB treatment, while PEG-IFN and emtricitabine are not licensed for HBV treatment in most European countries. Because of their possible teratogenicity, only drugs classified in category C or B can be used during gestation. According to FDA classification, lamivudine, entecavir and adefovir are classified as 'C', while telbivudine and tenofovir are classified as drugs of category B (Table 3). Until now, the more appropriate drug is tenofovir because many data are available about the safety profile in pregnancy. Furthermore, several data above safety of tenofovir are reported in HIV patients showing very low rate of congenital abnormalities. By contrast, PEG-IFN is absolutely contraindicated because of high teratogenicity risk. In fact, women or partners of patients treated with PEG-IFN or in childbearing age should use a good contraception system until three to 6 months after stopping antiviral therapy.
Regarding to the different pharmacological features and teratogenicity risks of drugs for treating a young woman chronically HBV infected that wish to become pregnant should dispose her pregnancy and should be educated about safety profile of drugs during pregnancy. According to the last EASL guidelines, the therapeutic approach may be different based on the severity of liver damage: in women that want to become pregnant and do not have an advanced fibrosis, it is advisable to delay therapy after the delivery; in women with an advanced fibrosis or cirrhosis, therapy is mandatory. During pregnancy, therapy must be based on a NA of category B, possibly tenofovir. If pregnancy is accidental and not planned, therapy should be adjusted and modified with a NA of category B.
HBV infection can be transmitted from mother-to-foetus at delivery. This risk, as mentioned before, correlates with viral load and HBeAg positivity. The prevention of HBV perinatal transmission is traditionally based on the combination of passive and active immunization with HBIG and HBV vaccination. Such a strategy, however, may not be effective in a proportion of newborns from highly viremic women (serum HBV-DNA >10 copies/mL), which carry a risk of vertical HBV transmission more than 10% despite administration of HBIG and vaccination. In these cases, the use of NAs before delivery may reduce viral loads and therefore improve the effectiveness of HBIG and vaccination.
Therapy with lamivudine and, more recently, with telbivudine during the last trimester in HBsAg-positive women with high viral load has been shown to be safe and to reduce the risk of intrauterine and perinatal transmission of HBV if given in addition to passive and active vaccination by HBIG and HBV vaccination after delivery. No controlled clinical trial of tenofovir to prevent perinatal transmission has been carried out until now.
There is not contraindication of breastfeeding for HBsAg-positive mother, even if HBV-DNA has been found in maternal milk. No studies are available about safety of NAs use during the breastfeeding. For mothers on antiviral therapy with lamivudine or tenofovir, breastfeeding is not recommended because few data are available about the safety of antiviral exposure during breastfeeding; however, due to low oral bioavailability of tenofovir in maternal milk, the newborn should not considered to be at risk.
As regarding to HBV/HDV co-infection, clinical course of HDV infection in pregnancy is similar in pregnant and nonpregnant women, although the clinical suspicion of this possible disease should arise in pregnant women with acute or chronic hepatitis B with a reactivation or hypertransaminasemia, testing for anti-HDV. This is extremely uncommon; however, because the vaccination for hepatitis B, when given to newborns infants, is almost uniformly effective against hepatitis D. Vertical transmission has not been shown, so early delivery is not necessary. Breastfeeding is safe, and vertical transmission can be avoided using HBV immunoprophylaxis.
Prevalence of HCV infection in pregnant women ranges between 1% and 2% in the United States and Europe, but it could increase up to 8% in some developing countries. HCV mother-to-child transmission (MTCT) has been clearly documented, with reported rates of about 5–10%.
Pathogenesis of HCV infection in pregnancy and during the neonatal period remains poorly understood. During gestation, a modulation of immune responses differs between the different stages of pregnancy. In fact, at the same time, the maternal immune system must develop tolerance to paternal alloantigens to prevent maternal immune aggression against the foetus and maintain active immunity against HCV to protect both mother and foetus from the infection.
Although HCV affects a significant number of women of reproductive age, few studies have examined the impact of chronic HCV infection on pregnancy outcomes. Pregnancy does not seem to adversely affect the clinical course of HCV infection. The majority of pregnant anti-HCV-positive women are asymptomatic. It is possible to observe during pregnancy a decrease of aminotransferases and an increase of HCV viral load, followed by an inversion of parameters during the postpartum period. It has also been observed an increase of cases with cholestasis of pregnancy in anti-HCV-positive women. The benign course of disease observed during pregnancy is attributed to the production of endogenous IFN by foetus and placenta. The ALT levels decrease in association with viral load increase observed during the third trimester of pregnancy in women chronically infected by HCV could conceivably be explained by a pregnancy-associated decline in immune-mediated hepatocellular destruction and change of immunological state.
Multiple host factors have been shown to increase the risk of HCV MTCT; some of them are unchangeable, such as elevated viral load, co-infection with HIV, abuse of drugs and alcohol, other are mainly related to delivery management including amniocentesis and prolonged rupture of membranes. Viral transmission can occur both in the uterus and during delivery. Indeed, perinatal HCV transmission is almost restricted to women with detectable HCV-RNA in the peripheral blood and MTCT rarely occurs if the maternal viral load remains below 100 000 HCV-RNA IU/mL. However, there is a broad overlap in the levels of plasma HCV-RNA between transmitting and nontransmitting mothers.
The risk of vertical transmission is related to viral load. Hence, the achievement of viral clearance would be desirable before pregnancy because there are no drugs for HCV infection usable during gestation to reduce the risk of transmission.
Women with HCV infection can plan a pregnancy, and they must be educated about high teratogenicity risks of therapy during pregnancy. HCV-infected women, treated with standard therapeutic approach, must attend at least 6 months before becoming pregnant. If they accidentally become pregnant, therapy must be stopped and the mother should be informed for the risks of teratogenicity.
HCV-infected pregnant women do not need special monitoring, but only prenatal routine care as noninfected pregnant women. Delivery modalities usually do not influence vertical transmission, and Caesarean section is not considered a modality to prevent vertical transmission.
Data on transmission of HCV during lactation are contradictory. It has been suggested a correlation between disease activity (raised transaminases and HCV-RNA positive) and detection of HCV-RNA in breast milk resulting a chance of increased disease transmission by this route. On the other hand, in several studies, transmission of HCV by breastfeeding has not been demonstrated, so there are no specific contraindications of breastfeeding in HCV-infected women. Infected children can be treated with the available options but usually they can be treated only after the third year of age because of the adverse effects of treatment on growth. However, spontaneous resolution of infection has been observed both in mother during the postpartum period and in foetus.
No data have been published about safety of boceprevir and telaprevir in pregnant women. Their use is actually contraindicated in patients taking oral contraceptive containing ethinylestradiol and norethindrone so that alternative methods of nonhormonal contraception should be used.
Chronic Viral Hepatitis
Chronic viral hepatitis does not adversely affect the course of pregnancy, but it carries the risk of vertical transmission of the virus. Overall, chronic viral hepatitis is the most frequent pre-existing liver disease and they need to be followed through the whole period of pregnancy and overall after delivery.
HBV Infection
HBV is an important global health problem, because of high risk of perinatal viral transmission. Before the adoption of HBIG, approximately 70–90% of infants born to HBeAg-positive mothers may became chronically infected by HBV. HBV infection does not significantly modify the clinical course of pregnancy either fertility or conception unless the woman has liver cirrhosis or liver failure. Moreover, chronic HBV infection does not increase maternal or foetal morbidity and mortality, although a recent study has shown an increased risk of diabetes mellitus, ante-partum haemorrhages and life-threatening preterm labour. On the other hand, in the presence of cirrhosis, the risk to develop significant perinatal complications and poor pregnancy outcome is higher. Moreover, cirrhotic pregnant women have usually higher spontaneous rates of maternal complications such as placental abruption, gestational hypertension and peripartum haemorrhages. By the contrary, pregnancy does not influence the course of chronic HBV infection and usually it is not considered as a possible worsening factor.
Nowadays, the risk of perinatal transmission, which represents in many areas of the world the primary source of persistence of HBV chronic infection, has focused the attention to the management of HBV infection during pregnancy. The risk is very high in HBeAg-positive patients with high viral load, but conflicting data exist about the potential role of different HBV genotypes in influencing transmission.
Among maternal risk factors affecting vertical or perinatal transmission, we also mention placental diseases or complications appearing during labour and breastfeeding, which is another major source of infection.
Together with the immunoprophylaxis, the choice of correct antiviral therapy plays a major role in chronic HBV-infected women. Not all available drugs for treatment of chronic HBV infection can be used during pregnancy, and they have an important role to avoid an exacerbation of disease that can occur in case of drug discontinuation, especially soon after the delivery, with high risk of occurrence of fulminant hepatitis causing a life-threatening condition both for mother and foetus.
Drugs used for the treatment of chronic hepatitis B (CHB) include recombinant interferon (IFN), pegylated interferon (PEG-IFN) and Nucleos(t)ides analogues (NAs). NAs are classified as nucleosides (lamivudine, telbivudine, emtricitabine and entecavir) or nucleotides (adefovir and tenofovir). All these drugs have been approved in Europe for CHB treatment, while PEG-IFN and emtricitabine are not licensed for HBV treatment in most European countries. Because of their possible teratogenicity, only drugs classified in category C or B can be used during gestation. According to FDA classification, lamivudine, entecavir and adefovir are classified as 'C', while telbivudine and tenofovir are classified as drugs of category B (Table 3). Until now, the more appropriate drug is tenofovir because many data are available about the safety profile in pregnancy. Furthermore, several data above safety of tenofovir are reported in HIV patients showing very low rate of congenital abnormalities. By contrast, PEG-IFN is absolutely contraindicated because of high teratogenicity risk. In fact, women or partners of patients treated with PEG-IFN or in childbearing age should use a good contraception system until three to 6 months after stopping antiviral therapy.
Regarding to the different pharmacological features and teratogenicity risks of drugs for treating a young woman chronically HBV infected that wish to become pregnant should dispose her pregnancy and should be educated about safety profile of drugs during pregnancy. According to the last EASL guidelines, the therapeutic approach may be different based on the severity of liver damage: in women that want to become pregnant and do not have an advanced fibrosis, it is advisable to delay therapy after the delivery; in women with an advanced fibrosis or cirrhosis, therapy is mandatory. During pregnancy, therapy must be based on a NA of category B, possibly tenofovir. If pregnancy is accidental and not planned, therapy should be adjusted and modified with a NA of category B.
HBV infection can be transmitted from mother-to-foetus at delivery. This risk, as mentioned before, correlates with viral load and HBeAg positivity. The prevention of HBV perinatal transmission is traditionally based on the combination of passive and active immunization with HBIG and HBV vaccination. Such a strategy, however, may not be effective in a proportion of newborns from highly viremic women (serum HBV-DNA >10 copies/mL), which carry a risk of vertical HBV transmission more than 10% despite administration of HBIG and vaccination. In these cases, the use of NAs before delivery may reduce viral loads and therefore improve the effectiveness of HBIG and vaccination.
Therapy with lamivudine and, more recently, with telbivudine during the last trimester in HBsAg-positive women with high viral load has been shown to be safe and to reduce the risk of intrauterine and perinatal transmission of HBV if given in addition to passive and active vaccination by HBIG and HBV vaccination after delivery. No controlled clinical trial of tenofovir to prevent perinatal transmission has been carried out until now.
There is not contraindication of breastfeeding for HBsAg-positive mother, even if HBV-DNA has been found in maternal milk. No studies are available about safety of NAs use during the breastfeeding. For mothers on antiviral therapy with lamivudine or tenofovir, breastfeeding is not recommended because few data are available about the safety of antiviral exposure during breastfeeding; however, due to low oral bioavailability of tenofovir in maternal milk, the newborn should not considered to be at risk.
As regarding to HBV/HDV co-infection, clinical course of HDV infection in pregnancy is similar in pregnant and nonpregnant women, although the clinical suspicion of this possible disease should arise in pregnant women with acute or chronic hepatitis B with a reactivation or hypertransaminasemia, testing for anti-HDV. This is extremely uncommon; however, because the vaccination for hepatitis B, when given to newborns infants, is almost uniformly effective against hepatitis D. Vertical transmission has not been shown, so early delivery is not necessary. Breastfeeding is safe, and vertical transmission can be avoided using HBV immunoprophylaxis.
HCV Infection
Prevalence of HCV infection in pregnant women ranges between 1% and 2% in the United States and Europe, but it could increase up to 8% in some developing countries. HCV mother-to-child transmission (MTCT) has been clearly documented, with reported rates of about 5–10%.
Pathogenesis of HCV infection in pregnancy and during the neonatal period remains poorly understood. During gestation, a modulation of immune responses differs between the different stages of pregnancy. In fact, at the same time, the maternal immune system must develop tolerance to paternal alloantigens to prevent maternal immune aggression against the foetus and maintain active immunity against HCV to protect both mother and foetus from the infection.
Although HCV affects a significant number of women of reproductive age, few studies have examined the impact of chronic HCV infection on pregnancy outcomes. Pregnancy does not seem to adversely affect the clinical course of HCV infection. The majority of pregnant anti-HCV-positive women are asymptomatic. It is possible to observe during pregnancy a decrease of aminotransferases and an increase of HCV viral load, followed by an inversion of parameters during the postpartum period. It has also been observed an increase of cases with cholestasis of pregnancy in anti-HCV-positive women. The benign course of disease observed during pregnancy is attributed to the production of endogenous IFN by foetus and placenta. The ALT levels decrease in association with viral load increase observed during the third trimester of pregnancy in women chronically infected by HCV could conceivably be explained by a pregnancy-associated decline in immune-mediated hepatocellular destruction and change of immunological state.
Multiple host factors have been shown to increase the risk of HCV MTCT; some of them are unchangeable, such as elevated viral load, co-infection with HIV, abuse of drugs and alcohol, other are mainly related to delivery management including amniocentesis and prolonged rupture of membranes. Viral transmission can occur both in the uterus and during delivery. Indeed, perinatal HCV transmission is almost restricted to women with detectable HCV-RNA in the peripheral blood and MTCT rarely occurs if the maternal viral load remains below 100 000 HCV-RNA IU/mL. However, there is a broad overlap in the levels of plasma HCV-RNA between transmitting and nontransmitting mothers.
The risk of vertical transmission is related to viral load. Hence, the achievement of viral clearance would be desirable before pregnancy because there are no drugs for HCV infection usable during gestation to reduce the risk of transmission.
Women with HCV infection can plan a pregnancy, and they must be educated about high teratogenicity risks of therapy during pregnancy. HCV-infected women, treated with standard therapeutic approach, must attend at least 6 months before becoming pregnant. If they accidentally become pregnant, therapy must be stopped and the mother should be informed for the risks of teratogenicity.
HCV-infected pregnant women do not need special monitoring, but only prenatal routine care as noninfected pregnant women. Delivery modalities usually do not influence vertical transmission, and Caesarean section is not considered a modality to prevent vertical transmission.
Data on transmission of HCV during lactation are contradictory. It has been suggested a correlation between disease activity (raised transaminases and HCV-RNA positive) and detection of HCV-RNA in breast milk resulting a chance of increased disease transmission by this route. On the other hand, in several studies, transmission of HCV by breastfeeding has not been demonstrated, so there are no specific contraindications of breastfeeding in HCV-infected women. Infected children can be treated with the available options but usually they can be treated only after the third year of age because of the adverse effects of treatment on growth. However, spontaneous resolution of infection has been observed both in mother during the postpartum period and in foetus.
No data have been published about safety of boceprevir and telaprevir in pregnant women. Their use is actually contraindicated in patients taking oral contraceptive containing ethinylestradiol and norethindrone so that alternative methods of nonhormonal contraception should be used.
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