EXPLORE PAST ISSUES
Virology
Vol. 17 No 2 | Winter 2015
Feature
Viral hepatitis in pregnancy


This article is 5 years old and may no longer reflect current clinical practice.

Viral hepatitis is reported to be the most common form of liver disease in pregnancy. Australia and New Zealand are low-prevalence areas for viral hepatitis; but, particularly with inward migration from high-prevalence regions, a significant number of women with viral hepatitis in pregnancy are likely to be encountered in clinical practice. This article will focus on the most common viral hepatitides in Australia and New Zealand – hepatitis B and C – but hepatitis A, D and E will also be briefly discussed.

Hepatitis B

Incidence in pregnancy

The prevalence of hepatitis B (HBV) in Australia and New Zealand is low, with 0.1 per cent to two per cent of the general population infected. The prevalence in pregnancy largely mirrors that in the general population, but in pregnant immigrants this reflects the prevalence in their birth country. A recent Australian study reported an overall prevalence of HBV in pregnant women of 0.75 per cent, but rates of 6.5 per cent to 8.6 per cent in women from Asia and the Pacific.1

Impact of pregnancy on HBV

Acute HBV in pregnancy is uncommon and its course appears unaltered by pregnancy though the likelihood of progression to chronic carriage may be increased by pregnancy. In chronic HBV, women with cirrhosis are at increased risk of decompensation and variceal bleeding during pregnancy and advanced disease should be excluded in patients not previously assessed. However, most pregnant patients with chronic HBV will not have severe disease and, although hepatic flares or even acute liver failure may rarely occur, in the majority the liver disease will be unaffected by pregnancy. Postpartum flares are common, but usually mild and asymptomatic. In a recent Australian study postpartum flares occurred in 25 per cent of pregnancies, but alanine transaminase (ALT) was less than 5xULN in two-thirds of patients and all remained asymptomatic throughout.2

Impact on pregnancy of HBV

Studies of pregnancy outcomes in women with chronic HBV have produced inconsistent results with no adverse effect in some, but increased risk of obstetric complications and neonatal morbidity in others. A large Israeli study found increased rates of low birthweight, perinatal mortality, congenital malformations, premature rupture of membranes and placental abruption in women with chronic HBV.3 An increased incidence of threatened preterm labour, preterm birth and antepartum haemorrhage has also been demonstrated. Gestational diabetes also appears more common in women with chronic HBV.

Mother-to-child transmission

Mother-to-child transmission can occur in up to 90 per cent of cases without immunoprophylaxis. Risk of transmission correlates with maternal viral load, with transmission to 70–90 per cent of infants born to high viral load eAg+ve mothers, but only 10–40 per cent in infants born to low viral load eAg-ve mothers. Most transmission occurs at birth. As a consequence, immunoprophylaxis with HBV hyperimmune gamma globulin (HBIG) within 12 hours of birth and subsequent HBV vaccination provides up to 95 per cent protection against perinatal infection. However, immunoprophylaxis failure may occur in women with very high viral loads. A number of studies have demonstrated that immunoprophylaxis failure is frequent with a viral load >8 log copies/ml (7 log iu/ml), but unlikely below this level.4

With regards to obstetric management, there is no definite evidence caesarean section, rather than vaginal delivery, reduces transmission. Although HBsAg is detectable in breastmilk, perinatal infection rates are the same in breastfed infants as formula-fed infants and breastfeeding is not contraindicated in infants who have received immunoprophylaxis.

Treatment of HBV in pregnancy

Data from the Antiretroviral Pregnancy Register have suggested that the oral antivirals tenofovir and lamivudine are safe in pregnancy, without any increased risk of birth defects. Telbivudine also appears safe, though fewer studies are available. Adefovir and entecavir are avoided in pregnancy as safety data are lacking. Tenofovir is the drug of choice in pregnancy and in breastfeeding mothers as viral resistance is unreported and the drug does not appear at significant levels in breastmilk.

The use of antiviral drugs during pregnancy is indicated for control of maternal liver disease or to prevent mother-to-child transmission. In patients already on antivirals before conception or in early pregnancy, the options are to stop treatment or continue with a drug safe in pregnancy. Patients with advanced fibrosis or cirrhosis should continue antiviral treatment to avoid disease progression or decompensation. In patients without severe disease, continuing treatment is advised to prevent flares.

In patients with active disease (elevated ALT and HBV DNA >105 iu/ml) not on treatment, the use of antiretrovirals should be considered. In patients with inactive disease (normal ALT), but high viral loads, current national guidelines do not recommend treatment.5 6 However, there is now strong evidence that antivirals commenced in late pregnancy prevent transmission. Two recent studies, one using telbivudine and the other tenofovir, showed dramatic reduction of transmission rates in women with high pre-treatment viral loads.7 8 The use of tenofovir, or telbivudine from 28 weeks gestation should therefore be strongly considered in women with viral loads >7 log iu/ml. Continuation of treatment for up to 12 weeks after delivery to reduce postpartum flares and promote eAg seroconversion has been suggested. However, a recent Australian study showed no difference in the incidence of postpartum flares or eAg seroconversion rates whether antiviral treatment was stopped early, late or not used at all.9

Hepatitis C

Incidence in pregnancy

Approximately 2.7 per cent of the Australian and New Zealand population are positive for hepatitis C (HCV) antibodies, indicating prior exposure. Studies in Australian obstetric populations have shown anti-HCV positive rates from 1.1 per cent to 1.4 per cent. Of these women, 45–70 per cent will be chronically infected with virus.

Impact of pregnancy on HCV

There have been only rare reports of acute HCV during pregnancy, but these few case reports are not suggestive of a poorer outcome in pregnant individuals.

In chronic HCV infection, cirrhosis is associated with increased risk of decompensation and portal hypertensive bleeding during pregnancy. However, the majority of pregnant women with chronic HCV will not have advanced liver disease and therefore pregnancy will not adversely affect their liver disease. Indeed, elevated ALT in early pregnancy often normalises in late pregnancy, suggesting a decline in immune-mediated inflammatory activity during pregnancy. Transaminases typically rebound postpartum and there have been reports of worsening liver histology associated with this. However, overall, pregnancy appears to have little impact on the course of HCV-related liver disease.

Intrahepatic cholestasis of pregnancy (ICP) does appear to be associated with HCV infection. Women diagnosed with HCV have a >5-fold increase risk of ICP and it appears to occur earlier in pregnancy in women with chronic HCV.10

Impact of hepatitis C on pregnancy

The results of studies investigating the impact of chronic HCV on pregnancy outcomes have been conflicting. Some have not demonstrated any detrimental effect while others have shown a modest increased risk of adverse maternal and neonatal outcomes. Increased rates of preterm birth, low birthweight, need for neonatal assisted ventilation and need for neonatal ICU admission have been reported.11 Higher rates of gestational diabetes, gestational hypertension and antepartum haemorrhage have also been described.

Mother-to-child transmission

The rate of transmission of HCV from mother to child is low. In a recent meta-analysis the pooled risk of vertical transmission from HCV-ab positive/HCV RNA positive/HIV negative mothers was 5.8 per cent, but 10.8 per cent from HCV/HIV co-infected mothers.12 HCV viral load determines risk of transmission. Transmission does not occur from HCV-ab positive/HCV RNA negative women while in HCV RNA positive women, viral load correlates with transmission risk. A recent study showed transmission rates of 14.8 per cent at viral loads ≥6 log copies/ml, but only 3.9 per cent at viral loads below this level.

Premature rupture of membranes more than six hours before delivery and use of internal fetal monitoring have been shown to increase transmission risk.13 Vaginal delivery is not associated with higher risk of transmission then caesarean section.14

HCV does not appear to be transmitted from breastfeeding mothers to infants, despite HCV RNA being detectable in colostrum, and breastfeeding is therefore not contraindicated except in mothers with cracked or bleeding nipples.

Treatment during pregnancy

Pegylated interferon and ribavirin-based treatments for HCV are contraindicated in pregnancy. New oral antiviral agents, which are highly efficacious with few side effects, have been developed and are likely to be available soon. However, their safety in pregnancy has not yet been established. Furthermore, given the low rates of vertical transmission, treatment during pregnancy may not be warranted.

Hepatitis A

The incidence of acute hepatitis A (HAV) in the general population in Australia and New Zealand is low, but even in higher prevalence regions acute HAV in pregnancy is uncommon.

Pregnancy does not appear to adversely affect the course of acute HAV. However, pregnancy complications appear common, with reports of premature contractions and premature rupture of membranes in up to 69 per cent of pregnancies in acute HAV patients. Mother-to-child transmission of HAV may occur, and neonatal icteric hepatitis has been reported, but is uncommon owing to protective maternal anti-HAV IgG antibodies crossing the placenta.

There is no specific treatment for HAV and hence management is supportive. HAV vaccine is safe in pregnancy and should be considered in non-immune pregnant women travelling to endemic areas.

Hepatitis E

Hepatitis E (HEV) is the most common cause of viral hepatitis in pregnancy globally, particularly in hyper-endemic areas such as India. However, HEV is a rare cause of symptomatic hepatitis in Australia and New Zealand, but should be considered in pregnant women with acute hepatitis who have travelled to a high-prevalence area.

The course of acute HEV is worse in pregnant than non-pregnant women, and also worse than that of other viral hepatitides in pregnancy with fulminant hepatic failure (FHF) reported to be almost seven times more common in pregnant women than non-pregnant women HEV. Progression to fulminant hepatic failure has also been reported to be almost three times more common in pregnant women with HEV than in non-HEV acute hepatitis. Mortality is up to 20 per cent in pregnant women with acute HEV.

Acute HEV also worsens pregnancy outcomes: antepartum haemorrhage, intrauterine death and preterm delivery all occur at increased frequency. Vertical transmission of HEV has been reported to occur in up to 79 per cent of cases, with icteric or anicteric hepatitis developing in most infected infants, leading to death in almost 50 per cent.

There is no specific treatment for acute HEV, and management is therefore supportive. A safe, effective vaccine against HEV genotypes 1 and 4 has been developed (Hecolin®). Data from a small number of women suggest it is safe in pregnancy.

Hepatitis D

Hepatitis D (HDV) is a defective RNA virus that only exists as a co-infection with HBV. Approximately four per cent of HBV carriers worldwide have been exposed to hepatitis D. It is significant because both acute infection and chronic infection follow a more severe course than HBV mono-infection. In particular, chronic disease progresses more rapidly to cirrhosis.

Perinatal transmission is uncommon and nucleos(t)ide analogues are ineffective against HDV, but identifying pregnant patients with chronic HDV infection is important because of the increased likelihood of underlying advanced liver disease.

Conclusions

In the majority of women with viral hepatitis, pregnancy does not have a significant impact on their liver disease. However, it is still important to identify these patients given pregnancy outcomes may be negatively affected and also, in some cases, intervention may reduce the risk of the transmission of viral hepatitis to the infant.

References

  1. Reekie J, Gidding HF, Kaldor JM, Liu B. Country of birth and other factors associated with hepatitis B prevalence in a population with high levels of immigration. J Gastroenterol Hepatol. 2013;28:1539-1544.
  2. Giles M, Visvanathan K, Lewin S et al. Clinical and virological predictors of hepatic flares in pregnant women with chronic hepatitis B. Gut. 2014.
  3. Safir A, Levy A, Sikuler E, Sheiner E. Maternal hepatitis B virus or hepatitis C virus carrier status as an independent risk factor for adverse perinatal outcome. Liver Int. 2010;30:765-770.
  4. Wiseman E, Fraser MA, Holden S et al. Perinatal transmission of hepatitis B virus: an Australian experience. Med J Aust. 2009;190:489-492.
  5. RANZCOG. Management of Hepatitis B in Pregnancy. See: www.ranzcog.edu.au%2Fdoc%2Fmanagement-of-hepatitis-b-in-pregnancy.html .
  6. Digestive Disease Foundation/GESA. Australian and New Zealand Chronic Hepatitis B Recommendations. 2009.
  7. Han GR, Jiang HX, Yue X et al. Efficacy and safety of telbivudine treatment: an open-label, prospective study in pregnant women for the prevention of perinatal transmission of hepatitis B virus infection. J Viral Hepat. 2015.
  8. Chen HL, Lee CN, Chang CH et al. Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus. Hepatology. 2015.
  9. Nguyen V, Tan PK, Greenup AJ et al. Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare. Aliment Pharmacol Ther. 2014;39:1225-1234.
  10. Marschall HU, Wikstrom Shemer E, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. Hepatology. 2013;58:1385-1391.
  11. Pergam SA, Wang CC, Gardella CM, Sandison TG, Phipps WT, Hawes SE. Pregnancy complications associated with hepatitis C: data from a 2003-2005 Washington state birth cohort. Am J Obstet Gynecol. 2008;199:38.e1-38.e9.
  12. Benova L, Mohamoud YA, Calvert C, Abu-Raddad LJ. Vertical transmission of hepatitis C virus: systematic review and meta-analysis. Clin Infect Dis. 2014;59:765-773.
  13. Mast EE, Hwang LY, Seto DS et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis. 2005;192:1880-1889.
  14. Ghamar Chehreh ME, Tabatabaei SV, Khazanehdari S, Alavian SM. Effect of cesarean section on the risk of perinatal transmission of hepatitis C virus from HCV-RNA+/HIV- mothers: a meta-analysis. Arch Gynecol Obstet. 2011;283:255-260.

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