Perinatal Hepatitis B Virus Transmission
Perinatal transmission of HBV results in a high frequency of chronic infection, up to 90% in infants born to HBeAg-positive women. It is widely accepted that most perinatal transmission occurs at or near the time of birth, because neonatal vaccination prevents newborn infection in about 80–95% of cases. Theoretical risks for HBV transmission at delivery include exposure to cervical secretions and maternal blood. Transplacental (intra-uterine) transmission is presumed to cause the minority of infections not prevented by prompt immunization. Risk factors for transplacental transmission of HBV include maternal HBeAg positivity, HBsAg titre and HBV DNA level. In one study, a maternal HBV DNA level of ≥ 108 copies/ml was associated with increased likelihood of intra-uterine transmission. HBV is found in the villous capillary endothelial cells and the trophoblasts of the placenta, supporting the hypothesis that breach of the placental barrier is a mechanism for intra-uterine infection. Threatened preterm labour or spontaneous abortion, with the possible mixing of maternal and fetal blood, appears to increase the risk of HBV transmission. Recently, polymorphisms in some cytokine genes, such as those encoding for interferon-γ and tumour necrosis factor-α, have been correlated with risk of intra-uterine infection with HBV.[30,31] Prevention of perinatal transmission is considered critical in the attempt to decrease individual and population morbidity from chronic hepatitis B infection as well as the global burden of hepatitis B.
Mode of delivery has been examined as a potential risk factor for HBV transmission. In a report from China in 1988, of 447 infants born to HBsAg-positive women, 24.9% (96/385) of newborns delivered vaginally were HBV infected at birth, compared with < 10% (6/62) delivered by caesarean section. Both groups received HBV vaccine. These authors advised caesarean section delivery for mothers with high levels of viraemia. However, a later study compared outcomes among three groups: 144 infants born by spontaneous vaginal delivery, 40 by forceps or vacuum extraction and 117 by caesarean section. All infants received the HBIG and HBV vaccine at the recommended schedule. Chronic HBV infection was detected in the infants in 7.3, 7.7 and 6.8%, respectively, and response rates to immunization were similar in all groups. The authors concluded that mode of delivery does not influence the likelihood of HBV transmission. At this point, most obstetrical algorithms do not include change in the planned mode of delivery for HBsAg-positive women regardless of HBeAg status or level of viraemia.
In the USA, all pregnant women are supposed to be tested for HBsAg, regardless of assessed risk and previous testing. Neonates born to HBsAg-positive women should receive HBIG and vaccine before discharge and be followed to determine the adequacy of immune response and the vaccine failures. All infants, regardless of maternal HBsAg status, should receive HBV vaccine in the first months of life. In Taiwan, all infants have been receiving the HBV vaccine for almost 20 years, with a significant impact on perinatal transmission and childhood and adolescent infection and its complications.[34,35] Whether universal immunization will be adopted in all European countries, as the World Health Organization has recommended, depends on many factors, such as perceived prevalence and risk, changing immigration patterns, cost–benefit analyses and budgetary priorities.
Immunoprophylaxis provided to newborns clearly reduces the incidence of perinatal HBV transmission. In a recent meta-analysis of clinical trials, the relative risk of neonatal HBV infection in those who received HBV vaccine (plasma-derived or recombinant) was 0.28 [95% confidence interval (CI) 0.2–0.4] compared with those who received placebo or no intervention. Compared with vaccine alone, the addition of HBIG to the regimen further reduced the relative risk (0.54, 95% CI 0.41–0.73) when compared with active prophylaxis only. Nonetheless, there are clearly a substantial number of newborn infections, even with prompt administration of active and passive vaccination. The estimates vary, and depend on maternal HBeAg status, but most studies demonstrate anywhere from 1% to 10% chronic HBV infection in infants who were appropriately immunized. Clearly, with millions of at-risk pregnancies each year throughout the world, significant numbers of perinatally acquired chronic HBV infection are still occurring.
The major target for neutralizing anti-HBs is the a determinant of the surface antigen protein. Mutations in the S gene of HBV causing conformational changes in the a determinant have been detected in humans infected with HBV, and concern has been expressed that these variants might replicate in the presence of vaccine-induced anti-HBs or anti-HBs contained in HBIG.[38,39] At this point, no evidence suggests that S gene immunization escape mutants pose a threat to programmes using hepatitis B vaccines, but perhaps enhanced surveillance to detect the emergence of these variants will be necessary for monitoring the effectiveness of current vaccination strategies.
One approach to prevention of perinatal HBV transmission is provision of HBIG during pregnancy. Several reports have documented the results of this intervention, demonstrating varying efficacy.[27,41–43] Unfortunately, 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. Three of the four reports, however, documented a beneficial effect,[27,41,43] while in one no obvious difference was noted. One of the studies included examination of the effect of maternal HBIG receipt on the results of newborn vaccination, and found that maternal treatment with HBIG was associated with higher seroprotection (development of antibody to HBsAg, anti-HBs) rates in their offspring than observed in those whose mothers were not treated. Although a decrease in the perinatal HBV transmission rate was documented only in HBeAg-positive women, the beneficial effect on development of anti-HBs was seen in infants of both HBeAg-positive and HBeAg-negative women.
Because the risk of intra-uterine and perinatal transmission of HBV is clearly related to the level of maternal viraemia,[26,44] another strategy to interrupt this process is maternal treatment with a nucleoside analogue late in pregnancy. As stated above, the only HBV drug with a record of safe use in pregnant women is lamivudine. van Zonneveld et al. treated eight pregnant women with high HBV DNA levels with 150 mg lamivudine daily from gestational week 34 until delivery. The infants received both active and passive immunization at birth. The HBV DNA levels declined at least 1 log in five of the eight women, after 6–40 days. Although four of the infants were HBsAg positive at birth, all but one was negative by 12 months of age (12.5% transmission). The rate of chronic HBV infection in a comparable group of 24 historical controls was 28%. The largest study was a randomized, double-blind, placebo-controlled trial in 114 highly viraemic women, 68 of whom received lamivudine 100 mg daily beginning at week 32. Again, all infants received HBIG and vaccine in the standard regimen. Viral load reduction to < 1000 mEq/ml was achieved in 98% of the lamivudine-treated mothers and 31% of controls. At 1 year of age, 18% of infants of lamivudine-treated mothers were HBsAg positive, compared with 39% of those whose mothers received placebo. In addition, there was a greater incidence of anti-HBs positivity in infants whose mothers had been treated with lamivudine, 84 vs. 61% in controls. No adverse effects of lamivudine were noted in either the mothers or their infants.
At this point, there is no consensus regarding using HBIG or a nucleoside analogue in pregnant women to prevent perinatal transmission. One proposed algorithm includes consideration of both the level of maternal viraemia and the history of a previous child becoming infected with HBV perinatally.
Liver International. 2009;29(s1):133-139. © 2009
Cite this: Hepatitis B and Pregnancy: An Underestimated Issue - Medscape - Jan 01, 2009.