| Abstract|| |
There is a high global prevalence of hepatitis B. Perinatal transmission of hepatitis B is the predominant mode of transmission in high prevalence areas. The risk of progression to chronic liver disease and development of hepatocellular carcinoma in individuals who acquire the infection at birth is high. Perinatal transmission of hepatitis B can be reduced by early identification of hepatitis B virus (HBV) carrier mothers. High maternal viral loads and maternal serum HBeAg positivity increase the risk of perinatal transmission of hepatitis B. Passive and active immunoprophylaxis at birth reduces the risk of perinatal transmission of hepatitis B in approximately 95%. Failure of immunoprophylaxis has been related to possible in utero transmission of HBV. Reducing maternal HBV DNA levels by treatment with lamivudine in the last trimester of pregnancy in high viremic mothers may help reduce the risk of perinatal transmission of hepatitis B.
Keywords: Hepatitis B, immunoprophylaxis, transmission
|How to cite this article:|
Chowdhury SD, Eapen C E. Perinatal transmission of Hepatitis B. Hep B Annual 2009;6:80-8
| Introduction|| |
HBV infection is a major global health problem. An estimated 2 billion people have been infected worldwide, and more than 350 million suffer from chronic HBV infection.  Based on the prevalence of chronic hepatitis B, countries have been variably classified as high (≥8%), intermediate ((2%-7%), and low prevalence (≤2%) areas.  The predominant mode of transmission of hepatitis B in areas of high prevalence is perinatal. In intermediate prevalence areas, early childhood infection accounts for most chronic infections, whereas in low prevalence areas most infections are acquired in early adult life as a result of sexual exposure or intravenous drug use.
The prevalence of hepatitis B in India varies among the tribal (15.9%) and nontribal (2.4%) areas.  However, perinatal transmission is not restricted only to the tribal areas. Chakravarti et al in a study conducted in New Delhi found the incidence of perinatal transmission to be 29% and the incidence of HBsAg carriage due to perinatal transmission to be 17%.  One-third of the adult asymptomatic HBV carriers in India evolve directly from perinatal infection, whereas the majority become infected during childhood or early adulthood. 
Chronic infection with hepatitis B is more likely when the infection is acquired as infants. McMahon et al, in their study, found that the risk of becoming a carrier was inversely related to the age of the patient at the time of infection.  Ninety percent of infants born to hepatitis B surface antigen positive and hepatitis B e antigen positive mothers will become infected with hepatitis B.
| Screening of Pregnant Women|| |
Early recognition of HBV carrier status in expectant mothers helps in preventing maternal to fetal transmission of HBV. Sriprakash et al in a study done among 512 pregnant women attending a prenatal clinic identified 24 patients who were HBsAg positive. Six (25%) of the patients did not have any risk factor for HBV. They concluded that routine prenatal screening could prevent perinatal transmission of HBV.  Centers for Disease Control and Prevention recommends universal prenatal screening for hepatitis B after it noted that risk factor-based screening did not identify 35%-65% of all HBsAg positive mothers.  Thus screening the expectant mother could go a long way in prevention of perinatal HBV transmission.
Transmission of hepatitis B from the infected mother can occur through different routes:
- Transplacental (intrauterine)
- At delivery
| Transplacental Transmission of Hepatitis B|| |
This route probably accounts for a minority of cases of hepatitis B, which are not prevented by passive and active immunization at birth . The main risk factors for intrauterine HBV infection are maternal serum HBeAg positivity, history of threatened preterm labor, and the presence of HBV in the placenta, especially in the villous capillary endothelial cells. The rates of intrauterine transmission increases linearly with maternal serum HBsAg titers and HBV DNA concentration.  An increased risk of intrauterine transmission was also noted in patients who had polymorphisms in the TNF-α and IFN-γ gene. ,
The mechanism of intrauterine transmission of hepatitis B was studied by Zhang et al. In this study, 59 HBsAg-positive mothers and their newborns were taken as cases, and 10 HBsAg-negative mothers and their newborns served as control. Both HBsAg and HBcAg were detected in placentas from HBsAg-positive mothers. The concentration of the 2 antigens decreased from the mother's side to the fetus's side, in the following order: maternal decidual cells > trophoblastic cells > villous mesenchymal cells > villous capillary endothelial cells. But in 4 patients, the concentration was in the reverse order. The authors concluded that although the predominant route of intrauterine infection was transplacental, other routes of infection may exist.  In the past amniocentesis was considered to be a risk factor for intrauterine transmission. But subsequent studies by Alexander et al and Ko et al did not find any increased risk with amniocentesis. ,
Although the risk of intrauterine transmission of hepatitis B is very small, it still is an important mode of transmission as preventive strategies need to be instituted early on. Few studies done in China have shown that hepatitis B immunoglobulin administration to the infected mother may be useful in prevention of intrauterine transmission of HBV. ,
However, in another study done in China, 250 pregnant women who were seropositive for HBeAg were randomly divided into study (117 cases) and control groups (133 cases). Subjects in the study group received hepatitis B immunoglobulin (HBIg) 400 IU intramuscularly once a month for 3 months starting at 28 weeks. No treatment was given to the control group. All neonates received passive-active immunization after birth. No statistical differences were seen between the maternal HBsAg and HBV DNA levels of the study and control groups at labor or the protective efficacy rates (PER) of postnatal immunoprophylaxis at 12 months after birth (P > 0.05, respectively). The authors concluded that this regimen did not induce any adoptive immunoprophylaxis for the fetus; and it could not improve the PER of postnatal passive-active hepatitis B immunization. They also noted that a majority of the mother to child transmissions of HBV infection was at or after delivery.  Hsu et al suggested that surface gene mutants can emerge or be selected under the immune pressure generated by the administration of HBIg. 
As noted earlier, perinatal transmission of HBV as well as the PER of postnatal hepatitis B immunization is significantly related to the maternal prenatal HBV DNA levels.  Prenatal treatments with nucleoside analogs for women with high viremia may improve neonatal immunoprophylaxis. Lamivudine, a nucleoside reverse transcriptase inhibitor is a potent inhibitor of HBV replication. 
In a study by Li et al, similar rates of infection in patients receiving either lamivudine or HBIg were observed.  Xu et al, in a randomized double-blind placebo-controlled multicenter study, reported that lamivudine reduced HBV transmission from highly viremic mothers to their infants who received passive and active immunization. There were no adverse effects to lamivudine,  but a reduction in the maternal HBV levels does not guarantee nontransmission. In 2002, Kazmi et al reported an interesting case in which the child born to a HBV-positive mother in whom HBV DNA levels were suppressed to undetectable levels with nucleoside analogs was found to be infected with HBV. Using HBV DNA sequencing, complete sequence homology and a similar precore mutation were found in the mother and child, indicating vertical transmission.  Currently there is no recommendation regarding the use of either HBIg or nucleoside analogs during pregnancy. An algorithm proposed starting antivirals at 32 weeks, depending on a past history of perinatal HBV transmission. The threshold of treatment (HBV DNA levels) may be kept lower (>10 6 ) in patients with a prior history of perinatal HBV transmission than in those without a prior history of HBV transmission. 
| Transmission at Delivery|| |
It is widely accepted that most perinatal transmission of HBV occurs at or near the time of birth, because neonatal vaccination prevents new born infection in about 80%-95% of cases.  Underlying mechanisms for mother to child transmission of hepatitis B includes the transfusion of the mother's blood to the fetus during labor contractions, infection after the rupture of membranes, and direct contact of the fetus with infected secretions or blood from the maternal genital tract.
It was hypothesized that elective caesarean section (ECS) done prior to rupture of membrane or onset of labor, may help prevent this. Wang and colleagues did not find any difference on the effect of delivery mode on the interruption of maternal-infant transmission of HBV by immunoprophylaxis. They concluded that caesarean section does not reduce the incidence of immunoprophylaxis failure.  A systematic review was done of 4 studies (1 English and 3 Chinese) of parallel design, each conducted in a single center with ECS as intervention and vaginal delivery as control. It appeared that ECS was effective in preventing transmission during delivery. But, as all the included studies did not have any allocation concealment or blinding, nor any intention to treat analyses, the conclusions of the review need to be interpreted with great caution.  Currently there is no recommendation regarding the mode of delivery in HBsAg-positive patients.
The one intervention that has been proven to reduce the incidence of maternal to fetal transmission of hepatitis B is immunoprophylaxis. Lee et al, in a meta-analyses of 26 randomized control studies, found that vaccination reduced the occurrence of hepatitis B (RI 0.28, CI: 0.2-0.4). No significant difference was found between recombinant vaccine and plasma-derived vaccine (RI 1.00, CI: 0.71-1.42; 4 trials). Compared with placebo or no intervention, HBIg or the combination of plasma-derived vaccine and HBIg reduced hepatitis B occurrence (immunoglobulin RI 0.50, CI: 0.41-0.60, 1 trial; vaccine and immunoglobulin RI 0.08, CI: 0.03-0.17, 3 trials). 
Despite adequate passive and active immunization, approximately 10%-20% of children born to HBV-carrier mothers, especially those who are HBeAg-positive, become HBsAg carriers.  In utero transmission of HBV is considered one of the prime reasons for immunoprophylaxis failure. 
Another potential route of perinatal transmission of HBV is a possible vertical transmission from father to fetus. Wang et al, by using direct sequencing analysis of S gene 451 and C gene 2022, were able to demonstrate a father to child transmission.  Although this mode of transmission is a low risk, it may be one of the reasons for failure of at-birth immunoprophylaxis.
| Breast Feeding by a HBV-Positive Mother|| |
Lee et al, in 1978, demonstrated HBsAg by radioimmunoassay in 71% of breast milk samples in 125 healthy HBV carrier mothers. They recommended that breastfeeding should be avoided to prevent perinatal transmission. 
A study which compared 101 breastfed infants with 268 formula-fed infants born to HBV carrier mothers found that none of the breastfed and 9 of the formula-fed infants were positive for HBV after the initial vaccination series. Thus they concluded that breastfeeding posed no additional risk of transmission of HBV.  This was further validated in another study by Wang et al.  Thus, babies born to HBV carrier mothers who have received immunoprophylaxis at birth can be breastfed.
To conclude, surveillance of the expectant mother, with active and passive immunization of the child at birth would go a long way in the prevention of HBV infection.
| References|| |
|1.||thLavanchy D. Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention. J Clin Virol 2005;34:S1-3. |
|2.||Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507-39. |
|3.||Batham A, Narula D, Toteja T, Sreenivas V, Puliyel JM. Systematic review and meta-analysis of prevalence of hepatitis B in India. Indian Pediatr 2007;44:663-74. |
|4.||Chakravarti A, Rawat D, Jain M. A study on the perinatal transmission of the hepatitis B virus. Indian J Med Microbiol 2005;23:128-30. |
|5.||Nayak NC, Panda SK, Zuckerman AJ, Bhan MK, Guha DK. Dynamics and impact of perinatal transmission of hepatitis B virus in North India. J Med Virol 1987;21:137-45. |
|6.||McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al. Acute hepatitis B virus infection: Relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151:599-603. |
|7.||Sriprakash I, Anil TP. Routine prenatal screening of Indian women for HBsAg: Benefits derived versus cost. Trop Doct 1997;27:176-7. |
|8.||Centers for Disease Control (CDC). Prevention of perinatal transmission of hepatitis B virus: Prenatal screening of all pregnant women for hepatitis B surface antigen. MMWR Morb Mortal Wkly Rep 1988;37:341-6. |
|9.||Xu DZ, Yan YP, Choi BC, Xu JQ, Men K, Zhang JX, et al. Risk factors and mechanism of transplacental transmission of hepatitis B virus: A case-control study. J Med Virol 2002;67:20-6. |
|10.||Yu H, Zhu QR, Gu SQ, Fei LE. Relationship between IFN-gamma gene polymorphism and susceptibility to intrauterine HBV infection. World J Gastroenterol 2006;12:2928-31. |
|11.||Zhu QR, Ge YL, Gu SQ, Yu H, Wang JS, Gu XH, et al. Relationship between cytokines gene polymorphism and susceptibility to hepatitis B virus intrauterine infection. Chin Med J (Engl) 2005;118:1604-9. |
|12.||Zhang SL, Yue YF, Bai GQ, Shi L, Jiang H. Mechanism of intrauterine infection of hepatitis B virus. World J Gastroenterol 2004;10:437-8. |
|13.||Alexander JM, Ramus R, Jackson G, Sercely B, Wendel GD Jr. Risk of hepatitis B transmission after amniocentesis in chronic hepatitis B carriers. Infect Dis Obstet Gynecol 1999;7:283-6. |
|14.||Ko TM, Tseng LH, Chang MH, Chen DS, Hsieh FJ, Chuang SM, et al. Amniocentesis in mothers who are hepatitis B virus carriers does not expose the infant to an increased risk of hepatitis B virus infection. Arch Gynecol Obstet 1994;255:25-30. |
|15.||Zhu Q, Yu G, Yu H, Lu Q, Gu X, Dong Z, et al. A randomized control trial on interruption of HBV transmission in uterus. Chin Med J (Engl) 2003;116:685-7. |
|16.||Xiao XM, Li AZ, Chen X, Zhu YK, Miao J. Prevention of vertical hepatitis B transmission by hepatitis B immunoglobulin in the third trimester of pregnancy. Int J Gynaecol Obstet 2007;96:167-70. |
|17.||Yuan J, Lin J, Xu A, Li H, Hu B, Chen J, et al. Antepartum Immunoprophylaxis of three doses of hepatitis B immunoglobulin is not effective: A single-centre randomized study. J Viral Hepat 2006;13:597-604. |
|18.||Hsu HY, Chang MH, Ni YH, Lin HH, Wang SM, Chen DS. Surface gene mutants of hepatitis B virus in infants who develop acute or chronic infections despite immunoprophylaxis. Hepatology 1997;26:786-91. |
|19.||Gambarin-Gelwan M. Hepatitis B in pregnancy. Clin Liver Dis 2007;11:945-63. |
|20.||Li XM, Yang YB, Hou HY, Shi ZJ, Shen HM, Teng BQ, et al. Interruption of HBV intrauterine transmission: A clinical study. World J Gastroenterol 2003;9:1501-3. |
|21.||Xu WM, Cui YT, Wang L, Yang H, Liang ZQ, Li XM, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: A multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat 2009;16:94-103. |
|22.||Kazim SN, Wakil SM, Khan LA, Hasnain SE, Sarin SK. Vertical transmission of hepatitis B virus despite maternal lamivudine therapy. Lancet 2002;359:1488-9. |
|23.||Tram TT. Management of hepatitis B in pregnancy: Weighing the options. Cleve Clin J Med 2009;76:S25-9. |
|24.||Jonas MM. Hepatitis B and pregnancy: An underestimated issue. Liver Int 2009;29:133-9. |
|25.||Wang J, Zhu Q, Zhang X. Effect of delivery mode on maternal-infant transmission of hepatitis B virus by immunoprophylaxis. Chin Med J (Engl) 2002;115:1510-2. |
|26.||Yang J, Zeng XM, Men YL, Zhao LS. Elective caesarean section versus vaginal delivery for preventing mother to child transmission of hepatitis B virus: A systematic review. Virol J 2008;5:100. |
|27.||Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: Systematic review and meta-analysis. BMJ 2006;332:328-36. |
|28.||Wang JS, Chen H, Zhu QR. Transformation of hepatitis B serologic markers in babies born to hepatitis B surface antigen positive mothers. World J Gastroenterol 2005;11:3582-5. |
|29.||Wang S, Peng G, Li M, Xiao H, Jiang P, Zeng N, et al. Identification of hepatitis B virus vertical transmission from father to fetus by direct sequencing. Southeast Asian J Trop Med Public Health 2003;34:106-13. |
|30.||Lee AK, Ip HM, Wong VC. Mechanisms of maternal-fetal transmission of hepatitis B virus. J Infect Dis 1978;138:668-71. |
|31.||Hill JB, Sheffield JS, Kim MJ, Alexander JM, Sercely B, Wendel GD. Risk of hepatitis B transmission in breast-fed infants of chronic hepatitis B carriers. Obstet Gynecol 2002;99:1049-52. |
|32.||Wang JS, Zhu QR, Wang XH. Breastfeeding does not pose any additional risk of immunoprophylaxis failure on infants of HBV carrier mothers. Int J Clin Pract 2003;57:100-2. |
Sudipta Dhar Chowdhury
Department of GI Sciences, Christian Medical College Hospital, Vellore - 632004, Tamil Nadu
Source of Support: None, Conflict of Interest: None