Chronic hepatitis B virus (HBV) infection in pregnancy is an important global health problem. Over 50% of the 350 million chronic hepatitis B carriers acquire their infection perinatally [1, 2]. Without immunoprophylaxis, infants born to HBeAg-positive mothers have a 40–90% risk of vertical transmission . The risk of progression to chronic HBV infection is inversely proportional to the age at infection. Between 85 and 95% of infected infants develop chronic infection, whereas less than 5% of those who acquire infection during adulthood develop chronic infection [3-6]. Women of childbearing age with chronic HBV infection remain an important source of HBV transmission. Thus, the management of chronic HBV infection during pregnancy is an important opportunity to interrupt the perinatal transmission of HBV.
Because of the complex relationship between the physiological changes of pregnancy and the host immunological response to HBV, chronic HBV infection in pregnancy is a unique challenge . This review will provide an optimal approach to a number of issues of HBV management in pregnancy, including the prevention of perinatal transmission and the treatment of chronic hepatitis B in pregnancy.
Influence of hepatitis B virus infection on pregnancy
Hepatitis B virus infection does not significantly influence fertility or conception unless the patient has cirrhosis or liver failure . Moreover, HBV infection during pregnancy does not increase maternal or fetal morbidity and mortality. A study comparing 824 HBsAg-positive mothers to 6281 HBsAg negative but otherwise similar control mothers, found no difference in preterm delivery, birth weight, neonanatal jaundice, congenital anomalies or perinatal mortality . However, a recent case-control study showed that HBsAg-carrier mothers had an increased risk of gestational diabetes mellitus, antepartum haemorrhage and threatened preterm labour . This may be because a proportion of mothers with HBV-related active disease were included in the study. Chronic hepatitis B is associated with increased levels of proinflammatory cytokines [11, 12]. These systemic inflammatory responses may account for the adverse outcomes of pregnancy .
Pregnant women with cirrhosis have an increased risk of developing significant perinatal complications and having poor pregnancy outcomes . Pregnant women with cirrhosis have a higher spontaneous abortion rate, 30– 40% compared to 15– 20% in the general population [8, 15]. Pregnant women with cirrhosis also have higher rates of maternal complications, including gestational hypertension, placental abruption and peripartum haemorrhage compared to age-matched controls . Hepatic decompensation has been reported in 15% of mothers with liver disease .
Effects of pregnancy on hepatitis B virus-related liver disease
There is usually no worsening of liver disease during pregnancy. However, cholestasis, a chronic hepatitis B flare and liver failure have been rarely reported during pregnancy [14, 17, 18]. A normal pregnancy is associated with high levels of adrenal corticosteroids and oestrogen hormones resulting in increased HBV viraemia . These hormonal and cytokine changes can lead to minimal fluctuations in liver function tests. Serum alanine aminotransferase (ALT) tends to increase in late pregnancy and the postpartum period . Peripartum hepatitis flares leading to hepatic decompensation have been reported .
Risk of perinatal transmission of hepatitis B virus
Vertical transmission of HBV infection is the main source of chronic infection in endemic areas. As many as 90% of infants who acquire HBV infection from their mothers fail to clear the infection and develop chronic infection . Risk factors for mother to child transmission (MTCT) include both viral and host or maternal factors. In the clinical setting, HBeAg is used as an index for active viral replication and infectivity. Maternal HBeAg may be filtered through the placenta [20, 21]. Although HBeAg is detected in up to 70% of neonates, only 10% of these infants are actually infected at birth . Without HBV viraemia, most of these infants will clear HBeAg by 6 months of age . In the absence of immunoprophylaxis, the risk of MTCT of HBV infection is as high as 70–90% in infants born to HBeAg-positive mothers, and 10–40% for infants born to HBeAg-negative mothers [14, 23]. Serum HBV DNA levels are the most important independent risk factor for MTCT [24-28]. Results of studies on the effect of HBV genotype in MTCT have been conflicting and are still inconclusive [29-31].
Maternal factors are mainly related to the placenta. Prolonged uterine contractions during normal labour or threatened preterm labour may disrupt the placenta or result in transplacental leakage leading to maternal-fetal microtransfusions, thus increases the risk of MTCT [25, 28]. A first stage of labour of more than 9 h is associated with HBsAg positivity in cord blood . Mothers with a prior infant who failed immunoprophylaxis have a higher risk of transmitting HBV to their infants in subsequent pregnancies .
Mode of mother to child hepatitis B virus transmission
Hepatitis B virus can reach the fetus through the placental barrier; however, the impact of this mode of vertical transmission is not clear. Detection of HBsAg in cord or peripheral blood of newborns has been reported in 37% of those born to HBsAg-positive mothers . However, HBsAg positivity at birth did not predict subsequent HBV infection at 18 weeks or at 2 years of age . A Chinese study found that only 3.7% of babies tested HBsAg-positive at birth from intrauterine infection . Thus, intrauterine transmission is not the predominant mode of MTCT [14, 43]. However, intrauterine transmission cannot be prevented by HBV vaccine or HBIG given at birth, which is one important reason for the failure of immunoprophylaxis . HBV infection is transmitted to the placenta by a hematogenous route, then HBV spread in placental cells is cell-to-cell [35, 36]. Increased uterine contractions during a threatened abortion or threatened preterm labour can cause partial leakage of maternal blood into fetal circulation leading to HBV infection to the fetus [37-39].
Transmission during delivery
Transmission during delivery is the most frequent route of MTCT of HBV. Thus, the neonatal administration of HBIG and HBV vaccination can prevent HBV infection in more than 85% of the infants born to HBsAg-positive mothers . The mechanisms of HBV transmission may include micro-transfusion of mother's blood to the fetus during contractions, infection after the rupture of membranes and direct contact of the infant's mucosal membrane with the infected secretions or blood from the maternal genital tract . HBsAg is detected in 95% of the gastric fluids of infants born to HBV–infected mothers .
A total of 34% of infants born to HBeAg-positive mothers who are not infected at birth will acquire HBV infection in the next 6 months . Hepatitis B virus transmission in the post-partum period may be a result of close contact between the mother and baby [40, 42]. Breastfeeding is a major concern for transmission either through ingestion of HBV or by contact with skin lesions on the mother's breast milk samples [28, 43, 44]. However, several studies have shown that breastfeeding carried no additional risk of HBV transmission [45-48].