Perinatal transmission of hepatitis B virus: could hospitals be doing more?

Perinatal transmission remains a common route for hepatitis B infection

Hepatitis B virus (HBV) infection is an important public health problem, with more than 350 million people suffering from chronic infection worldwide, accounting for increased morbidity and mortality from cirrhosis, decompensated liver disease or hepatocellular carcinoma [1]. The route of HBV transmission has important clinical implications. Almost 90% of perinatally infected newborns will develop chronic, usually lifelong infection, whereas the risk of developing chronic infection from horizontal transmission during adulthood is less than 5%. In hyperendemic areas such as most of Asia and Africa, where the prevalence of chronic hepatitis B surface antigen (HBsAg) carriers reaches 8% or more, perinatal and early childhood transmission is the most common route of chronic HBV infection. In areas of low endemicity, perinatal and early childhood transmission may also account for more than one third of chronic infections [2]. Thus, it is crucial to prevent perinatal transmission of HBV via the identification of HBsAg-positive women and administration of immunoprophylaxis to their newborns.

Since the selective screening of high-risk pregnant women for HBsAg failed to identify a significant proportion of HBV-infected mothers [3], prenatal screening for HBsAg in all pregnant women was recommended by the CDC in 1988 [4]. Now, prenatal screening of pregnant women for HBsAg in the USA is nearly universal [5]; however, routine screening of pregnant women for HBsAg has not yet been conducted in prenatal care programs in some other countries, and even in Western countries, there are still some pregnant women who have never been tested for HBsAg [6,7].

In addition to prenatal screening of all pregnant women for HBsAg, vaccination of infants is a key strategy for the prevention of HBV infection. In 1992, the World Health Assembly passed a resolution calling for all the WHO Member States to integrate the hepatitis B vaccination into national immunization programs where feasible. The same year, the WHO set a goal for all countries to introduce the hepatitis B vaccine into national routine infant immunization programs by 1997 [8]. The US national guidelines have recommended that all newborns be vaccinated against HBV since 1991. In China, hepatitis B vaccine was first recommended for routine vaccination of infants in 1992, and it was added to the national immunization program in 2002. Since 2005, a new vaccination regulation has abolished all charges for hepatitis B vaccination of infants [9]. In 2006, the overall coverage of hepatitis B vaccine in infants reached more than 95.0% in urban and 83.0–97.0% in rural areas. The chronic HBsAg carrier rate in children less than 10 years of age decreased from 10.0% before the mass vaccination to 1.0–2.0%, and the rate in the general population decreased from 10.0 to 7.2% [10]. In 2008, a total of 177 (91.7%) of 193 countries had incorporated hepatitis B vaccine as an integral part of their national infant immunization programs [11].

The WHO position paper recommends that all infants should receive their first dose of hepatitis B vaccine as soon as possible after birth, preferably within 24 h, which is crucial in areas of high endemicity, but also as important in areas of intermediate and low endemicity [12]. However, only 27% of the 2006 birth cohort worldwide got their first dose within 24 h of birth [12], and only an estimated 69% of the 2008 birth cohort received the recommended three doses of hepatitis B vaccine [11]. A recent survey from the USA indicated that there were significant gaps persisting in hospital policies and practices to prevent perinatal HBV transmission. Efforts to avoid medical errors through appropriate implementation and monitoring of hospital practices are needed to eliminate perinatal HBV transmission [13]. By this token, perinatal transmission of HBV remains a common route for chronic infection, even though screening all pregnant women for HBsAg and hepatitis B vaccination for all children has been recommended for so many years.

Efficacy of hepatitis B vaccination & hepatitis B immunoglobulin to prevent perinatal transmission of HBV

The risk of perinatal HBV transmission in infants born to HBsAg-positive mothers is high without proper immunoprophylaxis; the highest risk (80–90%) is in infants born to hepatitis B e-antigen (HBeAg)-positive mothers, and the risk ranges from 10 to 40% among infants born to HBeAg-negative mothers [14].

A meta-analysis showed that hepatitis B vaccination was effective in reducing the risk of hepatitis B occurrence in newborns of HBsAg-positive mothers (relative risk: 0.28; 95% CI: 0.20–0.40) [15]. However, vaccination alone could not induce immunity against HBV in some infants born to HBsAg-positive, particularly HBeAg-positive mothers, and the risk of developing chronic HBV infection in infants born to HBeAg-positive mothers was more than 10–20%, despite hepatitis B vaccination [16,17].

Temporary immunity may be obtained by administering hepatitis B immunoglobulin (HBIG) for postexposure prophylaxis. HBIG alone has also been demonstrated to be effective in preventing HBV transmission [15], but with the availability of hepatitis B vaccine, HBIG is typically used as an adjunct to vaccination. HBIG prophylaxis in conjunction with HBV vaccination may be of additional benefit to infants born to HBsAg-positive, particularly HBeAg-positive mothers [16–18]. A meta-analysis has shown that combined immunoprophylaxis with hepatitis B vaccination and HBIG could significantly reduce hepatitis B occurrence in newborn infants compared with vaccination alone [15].

The Advisory Committee on Immunization Practices recommends that all infants born to HBsAg-positive women should receive HBIG and the first dose of hepatitis B vaccine within 12 h of birth, administered at different injection sites [19]. Despite adequate compliance with combined immunoprophylaxis with hepatitis B vaccination and HBIG, perinatal transmission of HBV still occurred in 5–10% of infants born to HBsAg-positive mothers. Some studies have shown that the failure of HBV immunoprophylaxis was significantly associated with maternal HBeAg positivity and high HBV DNA levels, therefore, additional measures were urgently needed to protect infants born to highly viremic women [17,18,20].

Role of antiviral therapy with nucleoside or nucleotide analogues in high-risk pregnant women

Given that the risk of perinatal transmission of HBV is clearly related to the level of maternal viremia, another strategy, in addition to combined immunoprophylaxis with hepatitis B vaccination and HBIG being given to the newborns, to prevent perinatal transmission of HBV is maternal antiviral therapy with a nucleoside or nucleotide analogue in late pregnancy to lower HBV DNA levels.

Among the approved nucleoside or nucleotide analogues, telbivudine and tenofovir are class B, while other drugs, including lamivudine, adefovir and entecavir, are class C. To date, no overall increase in prevalence or any specific pattern of congenital anomalies have been detected with the use of lamivudine or tenofovir through prospective voluntary reporting to the Antiretroviral Pregnancy Registry [21].

There have been several studies reporting the efficacy and safety of lamivudine to prevent perinatal transmission of HBV [22–24]. van Nunen et al. treated three highly viremic pregnant women with 150 mg of lamivudine daily from week 36 of pregnancy until delivery [22]. At birth, HBV DNA was not detectable by PCR in the three infants, both in capillary blood and in the cord blood sample, and remained negative, whereas HBV DNA was positive at birth in all newborns of untreated women. In another study, eight mothers with high HBV DNA levels (≥1.2 × 10⁹ geq/ml) were treated with 150 mg of lamivudine daily during the last month of pregnancy [23]. All newborns received HBIG and hepatitis B vaccination at birth and were followed up. Only one of the eight children (12.5%) born from these lamivudine-treated mothers was HBsAg- and HBV DNA-positive at the age of 12 months, whereas perinatal transmission occurred in seven out of 25 children (28%) in the untreated historical control group.

One randomized, double-blind, placebo-controlled study evaluated the efficacy of lamivudine given during late pregnancy to reduce perinatal transmission in highly viremic mothers [24]. A total of 150 mothers were randomized to either lamivudine 100 mg daily or placebo from week 32 of gestation to week 4 postpartum. At birth, infants received recombinant HBV vaccine with or without HBIG and were followed-up until week 52 after birth. In the primary analyses, where missing data were counted as failures, infants in the lamivudine + vaccine + HBIG group had a significant decrease in incidence of HBsAg positivity (10 out of 56, 18% vs 23 out of 59, 39%; p = 0.014) and in detectable HBV DNA (11 out of 56, 20% vs 27 out of 59, 46%; p = 0.003) compared with infants in the placebo + vaccine + HBIG group. Sensitivity analyses to evaluate the impact of missing data at week 52 resulting from a high dropout rate (13% in the lamivudine + vaccine + HBIG group and 31% in the placebo + vaccine + HBIG group) remained consistent with the primary analysis in that lower transmission rates were still observed in the infants of lamivudine-treated mothers, but the differences were not statistically significant. No safety concerns were noted in the lamivudine-treated mothers or their infants [24].

Despite suppression of HBV DNA to undetectable levels in the mother by prolonged lamivudine therapy, the newborn could still develop chronic HBV infection [25]. Up until now, there have been no convincing prospective controlled trials demonstrating the benefit of antiviral therapy in HBsAg-positive mothers to reduce the risk of perinatal transmission of HBV, particularly when combined immunoprophylaxis with HBIG and HBV vaccination is administered to the newborn. The studies indicate that lamivudine can be given safely during pregnancy, but an important and still unresolved issue is whether this approach is safe for the mother, the major issues being posttreatment flares of disease and development of antiviral resistance [26].

Role of maternal HBIG during pregnancy for prevention of HBV transmission

Besides exposure to cervical secretions and maternal blood as theoretical risks for HBV transmission at delivery, transplacental (intrauterine) transmission is presumed to cause the minority of infections not prevented by prompt immunoprophylaxis to the infants after birth.

Some studies have evaluated the role of maternal HBIG during pregnancy to prevent perinatal transmission of HBV, and demonstrated varying efficacy [27–30]. The studies are quite heterogeneous, using different doses and routes of HBIG administration, and utilizing different outcomes to determine neonatal infection, such as HBV DNA in cord blood or HBsAg in the infants at 6 months of age. In some studies, only HBeAg-positive mothers were included and in others HBeAg status was not specified. Therefore, even though some studies have shown that maternal HBIG during pregnancy may prevent intrauterine HBV infection, its accurate role is quite controversial and no committees have recommended the routine maternal HBIG during pregnancy to prevent perinatal transmission of HBV, even in women with high HBV DNA levels.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.