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http://www.gastrojournal.org/article/S0016-5085%2811%2901164-4/fulltext
Influence of Chronic HBV Infection on Pregnancy: A Human Model of Maternofetal Virus Host Interactions published online 24 August 2011.
Article Outline
Elefsiniotis IS, Tsoumakas K, Papadakis M, et al. (University Department of Internal Medicine, Hepatology Unit, Elena Venizelou Hospital, Athens, Greece). Importance of maternal and cord blood viremia in pregnant women with chronic hepatitis B virus infection. Eur J Intern Med 2011;22:182–186.
The study by Elefsiniotis et al, evaluated, spontaneous preterm birth rates and maternal-fetal transmission in a group of hepatitis B virus e antigen (HBeAg)-negative chronic HBV-infected pregnant women without known risk factors for preterm delivery (Eur J Intern Med 2011;22:182–186). The authors evaluated 138 chronic HBV-infected pregnant women who consecutively gave birth at the University Departments of Obstetrics and Gynaecology of the Alexandra Hospital and the Elena Venizelou Maternal and Perinatal Hospital of Athens, Greece, between July 2005 and December 2007, during the perinatal period. Maternal hepatitis B virologic tests (hepatitis B surface antigen [HBsAg], HBeAg, anti-HBe, anti-HBc, and anti-HBs) and HBV DNA levels (measured by Cobas Amplicor HBV Test, lower limit of quantification: 300 copies/mL) were done. Cord blood obtained at the time of delivery was tested for HBsAg and HBV DNA. All neonates received hepatitis B immune globulin (0.6 mL/kg) and vaccinated against HBV with the first dose of vaccine (10 μg) within 24 hours of delivery and the vaccination schedule continued with 3 more doses of the vaccine at months 1, 2, and 7. Infants were evaluated at 12 months both serologically (HBsAg, anti-HBc, anti-HBs) and virologically (HBV DNA). Transmission of HBV infection to infants was confirmed by detectable HBsAg in their serum and/or HBV DNA positivity at the age of 12 months. Infants with isolated anti-HBs positivity (anti-HBs ≥ 10 μIU/mL) at month 12 of life were considered fully protected. Infants with HBsAg negativity but without isolated anti-HBs positivity at month 12 of life were reevaluated at months 18 and 24.
Thirty-six pregnant women were excluded owing to reasons such as HBeAg-positive chronic HBV infection, history of preterm birth, non-singleton pregnancy, known pregnancy-related complications, and other known bacterial, fungal, parasitic, or viral infections.
Spontaneous preterm birth was observed in 15 of 102 (14.7%) of the HBeAg-negative, chronic HBV-infected pregnant women. Age, hemoglobin, white blood cell count, platelet count, aspartate aminotransferase and alanine aminotransferase (ALT) levels of the pregnant women were comparable between those with and without preterm birth. Lymphocyte count was significantly lower in women with preterm birth as compared with those without preterm birth (median count, 1357 vs 1740/mm3, respectively; P = .006). HBV DNA was detectable (>300 copies/mL) in 49 of 76 women (64.5%) in whom serum HBV DNA levels during the perinatal period were available. Detectable HBV DNA (>300 copies/mL) was observed in 42 of 67 women (62.7%) without preterm birth and in 7 of 9 women (77.8%) with preterm birth (P = .478). Median HBV DNA levels were also comparable between women with or without preterm birth (7680 vs 2130 copies/mL; P = .152).
Data concerning cord blood HBV DNA and HBsAg were available in 73 and 89 women, respectively. HBV DNA and HBsAg were detectable in 13 (17.8%) and 29 (32.6%) cord blood samples evaluated, respectively. HBsAg was detected in the cord blood of 2 of 13 women (15.4%) with preterm birth and 27 of 76 women (35.5%) without preterm birth (P = .208). HBV DNA was detected in the cord blood of 5 of 9 women (55.6%) with preterm birth and in 8 of 64 women (12.5%) without preterm birth (P = .007). However, the median cord blood HBV DNA was comparable among women with or without preterm birth (316 vs 347 copies/mL, respectively; P = .404).
The median maternal serum HBV DNA was significantly higher among women with detectable HBV DNA in their cord blood compared with those with undetectable HBV DNA in cord blood (147.543 vs 1.646 copies/mL, respectively; P = .002). Women with serum HBV DNA ≥10,000 copies/mL during the perinatal period had a 5.8 times higher risk of HBV DNA presence in their cord blood compared with women with serum HBV DNA <10,000 copies/mL (P = .003).
The relative risk of HBV DNA in cord blood was 6.43 times higher in women with serum HBV DNA ≥10,000 copies/mL and absolute lymphocyte count <1500 (5/7; 71.4%) compared with women with all the other combinations of HBV DNA and absolute lymphocyte count (P = .001; Eur J Intern Med 2011;22:182–186).
Overall, 44 infants completed the vaccination schedule and were evaluated at 12 months. All were HBsAg-negative and had undetectable HBV DNA levels, 12 of 44 (27.3%) exhibited isolated anti-HBs positivity. The remaining 32 infants exhibited anti-HBc positivity, with (19/32) or without (13/32) the presence of anti-HBs. At month 18, only 2 infants had anti-HBc positivity, and at month 24 all infants had isolated anti-HBs positive serologic status.
Back to Article Outline Comment Approximately 400 million people are chronically infected with HBV worldwide and almost half have acquired their infections either through mother-to-infant transmission or in early childhood, especially in countries where HBV has intermediate to high prevalences.
HBV infection in pregnancy provides a unique human model where host viral interactions can be studied. In fact, 4 main issues need to be addressed in a pregnant women harboring chronic HBV infection: The impact of HBV infection and HBV DNA levels on pregnancy, frequency and outcome of transmission of HBV infection to the newborn, short- and long-term outcome of HBV vaccination in the infant, and post-partum immune restoration and viral clearance in the mother.
Impact of HBV Infection and HBV DNA Levels on Pregnancy Many reports are available with varied results on the effects of chronic HBV infection on the outcome of pregnancy. Although few reports found no association of HBV infection with adverse pregnancy outcomes in chronically HBV-infected mothers, a few studies from Hong Kong and Israel have found that chronic HBV-infected mothers have increased risk for threatened preterm labor and preterm delivery (J Hepatol 2005;43:771–775; Liver Int 2010;30:765–770). However, these studies did not assess maternal HBeAg status or serum or cord blood HBV DNA levels during pregnancy. The study by Elefsiniotis et al showed a significant association between spontaneous preterm birth and presence of HBV DNA in the cord blood. HBV DNA positivity in cord blood was significantly associated with maternal HBV DNA levels (P = .002). In women with preterm labor, high concentrations of many cytokines in the vaginal or cervical secretions or serum, including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-8, and serum ferritin, are associated with early preterm delivery (Lancet 2008;371:75–84). Chronic HBV infection is associated with increased levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-10, macrophage migration inhibitory factor, and TNF-α (Hepatogastroenterology 2000;47:1675–1679). The findings of the association between the maternal chronic HBV infection with preterm birth and other reported obstetric complications including fetal distress, meconium peritonitis, and gestational diabetes could represent the effect of an accentuated systemic inflammatory response (J Hepatol 2005;43:771–775; Liver Int 2010;30:765–770). The low-grade inflammatory response may also explain the association of preterm birth with the absolute lymphocyte count. Although the study by Elefsiniotis et al focused on HBeAg-negative mothers, these findings regarding preterm birth could probably be extrapolated safely to HBeAg-positive chronic HBV-infected mothers as well. The role of HBV genotypes and naturally occurring HBV variants in this context needs to be studied. Many studies have suggested the use of nucleos(t)ide analog therapy with an appropriate anti-HBV agent for managing HBV infection in mothers whose serum tests positive for HBsAg and who have high serum HBV DNA concentrations in last trimester (Obstet Gynecol 2010;116:147–159). Whether the use of antiviral agents in chronic HBV-infected mothers with high serum HBV DNA concentrations throughout or during the last trimester of pregnancy, could result in lower obstetric complications including preterm birth is an interesting area.
Mother-to-Infant Transmission There are 3 possible routes of transmission of HBV from infected mothers to infants: Prenatal transmission (in utero), natal transmission (during delivery), and postnatal transmission (during child care or through breast milk; Hepatol Res 2010;40:31–48). In clinical practice, the tests of HBsAg and HBV DNA in fetal cord blood or neonatal peripheral blood are often performed to diagnose intrauterine HBV infection. Neonatal peripheral blood may be better than cord blood for diagnosis of intrauterine infection as the possibility of the cord blood being contaminated by the maternal blood always remains. Recent data indicate that the rate of intrauterine infection of HBV is 10%–79% (World J Gastroenterol 2004;10:437–4388; Pande C, Kumar A, Patra S, et al. Paper presented at Digestive Diseases Week, 2008; abstract 252). Intrauterine HBV can infect all kinds of cells in placenta, with HBV transmission occurring either by HBV-infected cells from maternal decidua to villous capillary endothelia or by HBV-infected trophoblastic cells directly to villous mesenchymal cells and villous capillary endothelial cells. High level of serum HBV DNA (irrespective of HBeAg status) in pregnant women is among the high-risk factors for occurrence of HBV intrauterine infection (Pande C, Kumar A, Patra S, et al. Paper presented at Digestive Diseases Week, 2008; abstract 252). This study found HBV DNA and HBsAg positivity in 17.8% and 32.6% of cord blood samples evaluated, respectively. A limitation of the present study is that neonatal peripheral blood was not analyzed in this study.
The most important determinant of prophylaxis failure has been shown to be maternal serum HBV DNA levels (viral load). Transmission rates as high as 32%, despite immunoprophylaxis, have been reported in infants born to mothers with HBV DNA concentrations >109 copies/mL (Obstet Gynecol 2010;116:147–159). Furthermore, there are reports which document transmission of HBV infection to newborns even at low maternal HBV DNA levels, although at a reduced frequency. A recent study from India found that HBV transmission (detection of any of the HBsAg, HBeAg, or HBV DNA in cord blood or peripheral blood of neonates) occurred in 78% of cases with maternal HBV DNA levels ≥1.5 × 105 copies/mL as compared with 47% in cases with maternal HBV DNA levels <1.5 × 105 copies/mL (Pande C, Kumar A, Patra S, et al. Paper presented at Digestive Diseases Week, 2008; abstract 252). One strategy for reducing vertical transmission of HBV infection is administering antivirals during pregnancy. A recent meta-analysis concluded that lamivudine in chronic HBV-infected mothers with a high degree of infectiousness in late pregnancy effectively prevented HBV intrauterine infection and mother-to-child transmission (Obstet Gynecol 2010;116:147–159). Thus, although most experience is with lamivudine, the use of other nucleos(t)ide analogs may be more desirable for prevention of HBV transmission during pregnancy, given the high resistance rate with use of lamivudine. Moreover all pregnant chronic HBV-infected mothers need not be treated; rather, mothers with high viremia in last trimester may be considered for antiviral treatment. Outcome of Immune Prophylaxis Mother-to-child transmission with prophylaxis failure is usually defined as HBsAg positive at 9–12 months of the immune prophylaxis schedule (Obstet Gynecol 2010;116:147–159). At present, the combined use of hepatitis B vaccine and high-titer hepatitis B immunoglobulin (HBIG) is generally recommended for neonatal prophylaxis. However, prophylaxis with hepatitis B vaccine alone (ie, without HBIG) may be as effective. Administration of hepatitis B vaccine in a 3- or 4-dose schedule without HBIG beginning ≤12 hours after birth has been demonstrated to prevent 70%–95% of perinatal HBV infections among infants born to HBsAg-positive women (Vaccine 2011;29:2846–2849). However, high transmission rates (23%–28%), despite immunoprophylaxis, have been reported in infants born to mothers with HBV DNA concentrations >5–9 log copies/mL (mainly HBeAg-positive mothers), especially in countries such as China and India (J Viral Hepat 2003;10:294–297). And two thirds of babies may still have occult HBV infection despite adequate anti-HBs titers. The long-term significance of occult HBV infection and mutations in the HBV sequences in these babies need to be studied further (Pande C, Kumar A, Patra S, et al. Paper presented at Digestive Diseases Week, 2008; abstract 252). The most important determinant of prophylaxis failure has been shown to be maternal serum HBV DNA levels (viral load; Pande C, Kumar A, Patra S, et al. Paper presented at Digestive Diseases Week, 2008; abstract 252; J Viral Hepat 2003;10:294–297). Variations in the S gene have been associated with failure of the HBV vaccine. The reported frequency of vaccine escape mutation in cases of perinatal transmission despite vaccination is 12%–39% (J Med Virol 2003;71:360–366). In the study by Elefsiniotis et al, despite the presence of HBV DNA and HBsAg in a proportion of cord blood samples evaluated (17.85% and 32.6%, respectively), the efficacy of the immunoprophylaxis schedule used was good. However, a limitation of the present study was that it had a small sample size and only HBeAg-negative mothers were included. The HBV DNA levels are quite low in HBeAg-negative chronic HBV-infected subjects compared with HBeAg-positive subjects (J Med Virol 2011;83:962–967). Only 14 women in this study population exhibited HBV DNA levels >10,000 copies/mL, and only 3 of them had HBV DNA levels >200,000 copies/mL. No details of the HBV status in newborn babies were provided in this study.
Genotype can be a factor associated with viral load and frequency of maternofetal transmission. Despite similar high prevalence of HBV in chronic HBV-infected mothers, the rate of maternofetal infection in east Asia, particularly China, is estimated to range between 10% and 88%, compared with ≤8% in studies conducted in sub-Saharan Africa. This difference can be largely attributed to the natural history of HBV infection of genotypes B and C; in Southeast Asia, infected individuals carry HBeAg and high viral load in age groups that include most women of gestational age. In contrast, in sub-Saharan Africa, whether infected with HBV genotype A1 or E, seroconversion to anti-HBe occurs before age 15 or 16, with the consequence that most women of gestational age carry anti-HBe (Hepatol Res 2010;40:31–48). Although genotypes A and D are prevalent in the areas where this study was conducted, a limitation of this study in the present context was lack of information on genotype distribution.
Post-Partum Immune Restoration and Viral Clearance Among pregnant patients with chronic HBV infection, generally there is an overall increase in median HBV DNA levels during pregnancy, which decline after pregnancy. ALT values also decrease during pregnancy and hepatic flares with or without HBeAg seroconversion (seroconversion rates varying from 12.5% to 17%) may occur within the first months after delivery (J Viral Hepatol 2008;15:37–41). Several factors produced by both the fetal trophoblast and the maternal uterine tissue (like CD95L, indoleamine 2,3-dioxygenase, and leukemia inhibitory factor) along with shift in the T helper (TH)1–TH2 balance toward a TH2 response and increase in regulatory T cells (Nat Immunol 2004;5:266–271), lead to tolerance against the hepatitis B virus during pregnancy with the observed rise in viral load and decline in ALT levels. All these changes in the immune status recover after delivery and the immune system fully restores its function. The reactivation of the immune system is responsible for the hepatic flares after pregnancy and the postpregnancy immune restoration syndrome remains a clinical curiosity. A limitation of this study was that no follow-up of mothers after delivery was provided. Large, prospective studies in the area of maternal–fetal transmission of HBV and immune modulations in the mother and baby are needed in this direction.
The current study has shown that the presence of HBV DNA in cord blood is significantly associated with spontaneous preterm birth in chronic HBV-infected pregnant women. Maternal chronic HBV infection is a risk factor on maternal and neonatal well-being, especially in areas with a high rate of HBsAg prevalence. More basic and clinical research is warranted to elucidate the potential role of chronic HBV infection in pregnancy complications, define the mechanisms by which maternal chronic HBV infection is related to preterm birth and other obstetric complications. Further research is needed in this readily available human model of ongoing, chronic infection to elucidate the potential mechanisms of intrauterine transmission, to study the feasibility of neonatal prophylaxis without HBIG, the role of viral factors (including genotype and mutations) in maternal-fetal transmission, and the mechanisms and impact of postpregnancy immune restoration syndrome. A relook at the manner in which efficacy of vaccination is assessed in infants born to mothers with HBV infection is also desirable. An entirely new field is waiting to be seized.
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发表于 2011-10-5 17:29