Discussion

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Screening for HBV Infection During Pregnancy

The hepatitis B vaccine was first licensed by the Food and Drug Administration (FDA) in 1981. The following year, the Advisory Committee on Immunization Practices (ACIP) recommended that the vaccine be given as part of an immunoprophylaxis regimen to prevent mother–to-child transmission of hepatitis B virus (HBV). In 1991, these recommendations expanded to include universal hepatitis B immunization for all children, regardless of the mother’s hepatitis B surface antigen (HBsAg) status, including the recommendation that all neonates receive hepatitis B vaccine at birth or before discharge from the hospital [1]. Currently, the ACIP, the American College of Obstetrics and Gynecology (ACOG), the American Academy of Family Practice (AAFP), and the American Academy of Pediatrics (AAP) recommend that all pregnant women receive prenatal testing for hepatitis B during each pregnancy by screening serum for the presence of HBsAg, regardless of risk factors or immunization history [2,3]. In addition to screening for prenatal HBsAg in the first trimester, testing should be repeated late in pregnancy for those women who tested negative if they have clinical and laboratory evidence of hepatitis or have ongoing risk for acquiring HBV infection (Figure 1). Pregnant women who present at delivery with unknown HBsAg status should have blood drawn at that time for HBsAg testing. In most states, hepatitis B infection in pregnancy is a reportable condition, and state and local public health departments have programs to provide education and follow-up for HBsAg positive women and their children. Mothers who have a positive HBsAg test should undergo evaluation to determine if they have evidence of chronic liver disease. To facilitate immunoprophylaxis of a woman who is HBsAg seropositive, provide a copy of her laboratory report to her delivery hospital and/or the obstetrical provider that will attend her devlivery, as well as the healthcare provider who will care for her neonate.

Risk of Perinatal HBV Transmission

The overall rate of transmission of HBV from an infected HBsAg-positive mother to her neonate during the perinatal period ranges from 5-90% in the absence of immunoprophylaxis [2,4-7]. This risk depends on whether the mother also has a positive hepatitis B e antigen (HBeAg) test; those with a positive HBeAg test have a transmission rate of 70-90%, whereas those with a negative HBeAg test have a rate of transmission less than 10% [2]. In these mothers with HBeAg, the risk of HBV perinatal transmission is reduced from 70-90% to approximately 5-15% when the infant receives postnatal immunoprophylaxis with both hepatitis B immune globulin (HBIG) and hepatitis B vaccine series [5,6]; the risk is reduced to approximately 20% with regimens that use multiple doses of HBIG only or the vaccine series alone [1,2, 4-6]. Although controlled trials have not been performed with HBeAg-negative women, postexposure prophylaxis with HBIG and vaccination would presumably further minimize the risk of transmission.

Route and Timing of Perinatal HBV Transmission

The precise mechanism of HBV transmission remains unclear, but it appears that infection may occur intrapartum or, rarely, in utero. Hepatitis B viral DNA and HBsAg have been detected in amniotic fluid, placental cells, and vaginal secretions of HBsAg-positive women during pregnancy and in cord blood of their neonates [7-10]. The mode of delivery (vaginal versus caesarean) does not appear to have an impact on the risk for perinatal HBV infection [11]. Transmission of HBV through breast milk is not a significant source of infection, as demonstrated by several small studies performed before the era of routine neonatal prophylaxis [12,13]. The relatively high efficacy of postnatal immunoprophylaxis corresponds with the theory that most mother-to-child HBV transmission presumably occurs during or shortly before delivery.

Prevention in Utero and During Delivery

The occurrence of breakthrough infections despite appropriate immunoprophylaxis, especially among children born to mothers with hepatitis B e antigen, has prompted investigators to explore additional methods for preventing vertical transmission, including administering HBIG,or lamivudine (Epivir-HBV), or both during pregnancy. Published studies evaluating the efficacy of these treatments for the prevention of perinatal HBV infection have shown reductions in HBV DNA levels and decreased rates of infection among infants born to treated mothers, but these studies used non-standard perinatal prophylaxis methods or had a small sample size [14-18]. Accordingly, further studies are needed to evaluate treatment in HBsAg-positive women, particularly those who also have a positive HBeAg and/or high HBV DNA levels. Few published studies have evaluated the risk of intrauterine infection associated with amniocentesis, but since HBV DNA has been detected in amniotic fluid and placental tissue, amniocentesis should be avoided if possible [19,20].

Management of Neonates

The 2005 ACIP recommendations regarding immunoprophylaxis to prevent HBV infection of neonates differ depending on the HBsAg status of the mother [2]. Note that single-antigen hepatitis B vaccine should be used for the birth dose and this dose is considered part of post-exposure prophylaxis for intrapartum exposure to HBV. The HBsAg-containing combination vaccines can be used for subsequent doses given to children six weeks of age and older.

Mother is HBsAg Positive (Figure 2)
1. Give 0.5 mL of HBIG and 0.5 mL of single-antigen hepatitis B vaccine within 12 hours of birth. Both HBIG and vaccine should be given intramuscularly at different sites.
2. Give subsequent doses of hepatitis B vaccine according to the ACIP schedule for a child born to a mother who is HBsAg positive.
3. All children born to women who are HBsAg positive should receive follow-up to ensure the child has completed the vaccine series and that immunoprophylaxis was successful.
4. Test for HBsAg and hepatitis B surface antibody (anti-HBs) 1-2 months after completing at least three dose in the HBV vaccine series (e.g. at 9-18 months of age, generally at the next well-child visit).
  1. Screening should not be performed before 9 months of age, or earlier than 4 weeks following the last vaccine dose.
  2. Children with anti-HBs levels 10 mIU/mL or greater have responded appropriately to the vaccine series and thus do not need additional follow-up.
  3. Children with anti-HBs levels less than 10 mIU/mL should be revaccinated with a second three-dose hepatitis B series and retested for anti-HBs 1-2 months after completing the vaccine series.
  4. HBsAg positive children will need life-long follow-up for their HBV infection.
5. Low birth weight infants (less than 2000 grams) should receive a single-antigen birth dose but this dose should not be counted towards the three dose series. The full three dose series should be started at 1-2 months of age; thus, these children should receive a total of four vaccine doses due to the theoretical risk of a poor immune response to immunization.
  1. Test for HBsAg and hepatitis B surface antibody (anti-HBs) 1-2 months after completing the fourth dose in the HBV vaccine series and then manage as in 1.d.i-iii.
Mother Has Unknown HBsAg Status at Time of Birth (Figure 3)
1. Begin the single-antigen hepatitis B vaccine series within 12 hours of birth while the mother’s HBsAg test is pending.
2. If the mother’s HBsAg test result is positive, the child should receive 0.5 mL of HBIG intramuscularly as soon as possible (within seven days of birth) and the vaccine series and screening should be completed according to the ACIP schedule for a child born to a mother who is HBsAg positive.
3. If the mother’s HBsAg test result is negative, the child should receive the routine series of preventive hepatitis B vaccine, with 0.5 mL of single-antigen hepatitis B vaccine administered intramuscularly before the infant is discharged from the hospital.
4. Low birth weight infants (less than 2,000 grams) should receive both single-antigen hepatitis B vaccine and HBIG (0.5 mL) if the mother's HBsAg status cannot be determined within 12 hours of birth. The birth dose of vaccine should not be counted towards the three dose series. The full three dose series should be started at 1 months of age; thus, these children should receive a total of four vaccine doses due to the theoretical risk of a poor immune response to immunization.
  1. Test for HBsAg and hepatitis B surface antibody (anti-HBs) 1-2 months after completing the fourth dose in the HBV vaccine series and then manage as in 1.d.i-iii.
Mother is HBsAg Negative (Figure 4)
1. Give 0.5 mL of single-antigen hepatitis B vaccine intramuscularly before the infant is discharged from the hospital and complete the series according to the ACIP schedule for childhood hepatitis B vaccine.
2. If a child is not immunized before discharge, single-antigen vaccine should be given within a month of birth and the series should be completed according to the ACIP schedule for childhood hepatitis B vaccine.
3. Medically stable, low birth weight infants (less than 2,000 grams) should receive their first dose 1 month after birth (or if the infant has showing consistent weight gain leading to hospital discharge prior to 30 days of age, the first dose of hepatitis B vaccine should be given at the time of hospital discharge). The child should complete the remaining three doses of vaccine per the ACIP schedule for full term infants, making sure the 2nd dose is given at least 1 month after the first dose.

Low Birth Weight and Preterm Infants

Until 2003, the AAP routinely recommended that the birth dose of hepatitis B vaccine for preterm and low birth weight infants born to HBsAg negative mothers be delayed until the child weighed 2000 grams or reached two months of chronological age. Subsequent studies in the United States, Europe and the Middle East indicated that three doses of hepatitis B vaccine in medically stable, preterm, low birth weight, and very low birth weight infants provide protective levels of hepatitis B surface antibody (anti-HBs) that are comparable to full term infants. Based on these more current data, the AAP now recommends that children born to HBsAg negative mothers should receive the first dose of hepatitis B vaccine as early as 30 days of chronological age, regardless of gestational age or birth [21]. In addition, the AAP recommends that if the infant has shown consistent weight gain leading to hospital discharge prior to 30 days of age, the first dose of hepatitis B vaccine should be given at the time of hospital discharge. The remaining doses of the hepatitis B vaccine series should be completed on the same schedule as for full term infants, making sure the second dose is given at least 30 days after the initial dose (Figure 5) [21]. Once immunity develops from immunization, protective antibody persists for at least 10 years [22,23]. Currently, the ACIP does not recommend routine booster doses of hepatitis B vaccine for individuals immunized in childhood [1,2].

Impact of Perinatal HBV Transmission

Unlike adults who have a high rate of spontaneous clearance of HBV following acute infection, approximately 90% of children infected during the perinatal period develop chronic infection [24], and up to 25% will develop chronic active hepatitis as adults [25]. Susceptible children not infected in the perinatal period are at risk for infection from horizontal transmission of HBV in the first five years of life [26].

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Modified from: Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part II: immunization of adults. MMWR. 2006;55(RR-16):1-25.
Figure 1
Modified from: Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR. 2005;54(RR-16):1-31.

Figure 2
Modified from: Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR. 2005;54(RR-16):1-31.

Figure 3
Modified from: Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR. 2005;54(RR-16):1-31.

Figure 4
Modified from: Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR. 2005;54(RR-16):1-31.

Figure 5


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	Question \| Discussion \| References \| CME Credit \| CNE Credit Discussion Screening for HBV Infection During Pregnancy The hepatitis B vaccine was first licensed by the Food and Drug Administration (FDA) in 1981. The following year, the Advisory Committee on Immunization Practices (ACIP) recommended that the vaccine be given as part of an immunoprophylaxis regimen to prevent mother–to-child transmission of hepatitis B virus (HBV). In 1991, these recommendations expanded to include universal hepatitis B immunization for all children, regardless of the mother’s hepatitis B surface antigen (HBsAg) status, including the recommendation that all neonates receive hepatitis B vaccine at birth or before discharge from the hospital [1]. Currently, the ACIP, the American College of Obstetrics and Gynecology (ACOG), the American Academy of Family Practice (AAFP), and the American Academy of Pediatrics (AAP) recommend that all pregnant women receive prenatal testing for hepatitis B during each pregnancy by screening serum for the presence of HBsAg, regardless of risk factors or immunization history [2,3]. In addition to screening for prenatal HBsAg in the first trimester, testing should be repeated late in pregnancy for those women who tested negative if they have clinical and laboratory evidence of hepatitis or have ongoing risk for acquiring HBV infection (Figure 1). Pregnant women who present at delivery with unknown HBsAg status should have blood drawn at that time for HBsAg testing. In most states, hepatitis B infection in pregnancy is a reportable condition, and state and local public health departments have programs to provide education and follow-up for HBsAg positive women and their children. Mothers who have a positive HBsAg test should undergo evaluation to determine if they have evidence of chronic liver disease. To facilitate immunoprophylaxis of a woman who is HBsAg seropositive, provide a copy of her laboratory report to her delivery hospital and/or the obstetrical provider that will attend her devlivery, as well as the healthcare provider who will care for her neonate. Risk of Perinatal HBV Transmission The overall rate of transmission of HBV from an infected HBsAg-positive mother to her neonate during the perinatal period ranges from 5-90% in the absence of immunoprophylaxis [2,4-7]. This risk depends on whether the mother also has a positive hepatitis B e antigen (HBeAg) test; those with a positive HBeAg test have a transmission rate of 70-90%, whereas those with a negative HBeAg test have a rate of transmission less than 10% [2]. In these mothers with HBeAg, the risk of HBV perinatal transmission is reduced from 70-90% to approximately 5-15% when the infant receives postnatal immunoprophylaxis with both hepatitis B immune globulin (HBIG) and hepatitis B vaccine series [5,6]; the risk is reduced to approximately 20% with regimens that use multiple doses of HBIG only or the vaccine series alone [1,2, 4-6]. Although controlled trials have not been performed with HBeAg-negative women, postexposure prophylaxis with HBIG and vaccination would presumably further minimize the risk of transmission. Route and Timing of Perinatal HBV Transmission The precise mechanism of HBV transmission remains unclear, but it appears that infection may occur intrapartum or, rarely, in utero. Hepatitis B viral DNA and HBsAg have been detected in amniotic fluid, placental cells, and vaginal secretions of HBsAg-positive women during pregnancy and in cord blood of their neonates [7-10]. The mode of delivery (vaginal versus caesarean) does not appear to have an impact on the risk for perinatal HBV infection [11]. Transmission of HBV through breast milk is not a significant source of infection, as demonstrated by several small studies performed before the era of routine neonatal prophylaxis [12,13]. The relatively high efficacy of postnatal immunoprophylaxis corresponds with the theory that most mother-to-child HBV transmission presumably occurs during or shortly before delivery. Prevention in Utero and During Delivery The occurrence of breakthrough infections despite appropriate immunoprophylaxis, especially among children born to mothers with hepatitis B e antigen, has prompted investigators to explore additional methods for preventing vertical transmission, including administering HBIG,or lamivudine (Epivir-HBV), or both during pregnancy. Published studies evaluating the efficacy of these treatments for the prevention of perinatal HBV infection have shown reductions in HBV DNA levels and decreased rates of infection among infants born to treated mothers, but these studies used non-standard perinatal prophylaxis methods or had a small sample size [14-18]. Accordingly, further studies are needed to evaluate treatment in HBsAg-positive women, particularly those who also have a positive HBeAg and/or high HBV DNA levels. Few published studies have evaluated the risk of intrauterine infection associated with amniocentesis, but since HBV DNA has been detected in amniotic fluid and placental tissue, amniocentesis should be avoided if possible [19,20]. Management of Neonates The 2005 ACIP recommendations regarding immunoprophylaxis to prevent HBV infection of neonates differ depending on the HBsAg status of the mother [2]. Note that single-antigen hepatitis B vaccine should be used for the birth dose and this dose is considered part of post-exposure prophylaxis for intrapartum exposure to HBV. The HBsAg-containing combination vaccines can be used for subsequent doses given to children six weeks of age and older. Mother is HBsAg Positive (Figure 2) Give 0.5 mL of HBIG and 0.5 mL of single-antigen hepatitis B vaccine within 12 hours of birth. Both HBIG and vaccine should be given intramuscularly at different sites. Give subsequent doses of hepatitis B vaccine according to the ACIP schedule for a child born to a mother who is HBsAg positive. All children born to women who are HBsAg positive should receive follow-up to ensure the child has completed the vaccine series and that immunoprophylaxis was successful. Test for HBsAg and hepatitis B surface antibody (anti-HBs) 1-2 months after completing at least three dose in the HBV vaccine series (e.g. at 9-18 months of age, generally at the next well-child visit). Screening should not be performed before 9 months of age, or earlier than 4 weeks following the last vaccine dose. Children with anti-HBs levels 10 mIU/mL or greater have responded appropriately to the vaccine series and thus do not need additional follow-up. Children with anti-HBs levels less than 10 mIU/mL should be revaccinated with a second three-dose hepatitis B series and retested for anti-HBs 1-2 months after completing the vaccine series. HBsAg positive children will need life-long follow-up for their HBV infection. Low birth weight infants (less than 2000 grams) should receive a single-antigen birth dose but this dose should not be counted towards the three dose series. The full three dose series should be started at 1-2 months of age; thus, these children should receive a total of four vaccine doses due to the theoretical risk of a poor immune response to immunization. Test for HBsAg and hepatitis B surface antibody (anti-HBs) 1-2 months after completing the fourth dose in the HBV vaccine series and then manage as in 1.d.i-iii. Mother Has Unknown HBsAg Status at Time of Birth (Figure 3) Begin the single-antigen hepatitis B vaccine series within 12 hours of birth while the mother’s HBsAg test is pending. If the mother’s HBsAg test result is positive, the child should receive 0.5 mL of HBIG intramuscularly as soon as possible (within seven days of birth) and the vaccine series and screening should be completed according to the ACIP schedule for a child born to a mother who is HBsAg positive. If the mother’s HBsAg test result is negative, the child should receive the routine series of preventive hepatitis B vaccine, with 0.5 mL of single-antigen hepatitis B vaccine administered intramuscularly before the infant is discharged from the hospital. Low birth weight infants (less than 2,000 grams) should receive both single-antigen hepatitis B vaccine and HBIG (0.5 mL) if the mother's HBsAg status cannot be determined within 12 hours of birth. The birth dose of vaccine should not be counted towards the three dose series. The full three dose series should be started at 1 months of age; thus, these children should receive a total of four vaccine doses due to the theoretical risk of a poor immune response to immunization. Test for HBsAg and hepatitis B surface antibody (anti-HBs) 1-2 months after completing the fourth dose in the HBV vaccine series and then manage as in 1.d.i-iii. Mother is HBsAg Negative (Figure 4) Give 0.5 mL of single-antigen hepatitis B vaccine intramuscularly before the infant is discharged from the hospital and complete the series according to the ACIP schedule for childhood hepatitis B vaccine. If a child is not immunized before discharge, single-antigen vaccine should be given within a month of birth and the series should be completed according to the ACIP schedule for childhood hepatitis B vaccine. Medically stable, low birth weight infants (less than 2,000 grams) should receive their first dose 1 month after birth (or if the infant has showing consistent weight gain leading to hospital discharge prior to 30 days of age, the first dose of hepatitis B vaccine should be given at the time of hospital discharge). The child should complete the remaining three doses of vaccine per the ACIP schedule for full term infants, making sure the 2nd dose is given at least 1 month after the first dose. Low Birth Weight and Preterm Infants Until 2003, the AAP routinely recommended that the birth dose of hepatitis B vaccine for preterm and low birth weight infants born to HBsAg negative mothers be delayed until the child weighed 2000 grams or reached two months of chronological age. Subsequent studies in the United States, Europe and the Middle East indicated that three doses of hepatitis B vaccine in medically stable, preterm, low birth weight, and very low birth weight infants provide protective levels of hepatitis B surface antibody (anti-HBs) that are comparable to full term infants. Based on these more current data, the AAP now recommends that children born to HBsAg negative mothers should receive the first dose of hepatitis B vaccine as early as 30 days of chronological age, regardless of gestational age or birth [21]. In addition, the AAP recommends that if the infant has shown consistent weight gain leading to hospital discharge prior to 30 days of age, the first dose of hepatitis B vaccine should be given at the time of hospital discharge. The remaining doses of the hepatitis B vaccine series should be completed on the same schedule as for full term infants, making sure the second dose is given at least 30 days after the initial dose (Figure 5) [21]. Once immunity develops from immunization, protective antibody persists for at least 10 years [22,23]. Currently, the ACIP does not recommend routine booster doses of hepatitis B vaccine for individuals immunized in childhood [1,2]. Impact of Perinatal HBV Transmission Unlike adults who have a high rate of spontaneous clearance of HBV following acute infection, approximately 90% of children infected during the perinatal period develop chronic infection [24], and up to 25% will develop chronic active hepatitis as adults [25]. Susceptible children not infected in the perinatal period are at risk for infection from horizontal transmission of HBV in the first five years of life [26]. [Back to Question \| See References] CME Credit \| CNE Credit \| Back to Top	Modified from: Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part II: immunization of adults. MMWR. 2006;55(RR-16):1-25. Figure 1 Modified from: Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR. 2005;54(RR-16):1-31. Figure 2 Modified from: Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR. 2005;54(RR-16):1-31. Figure 3 Modified from: Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR. 2005;54(RR-16):1-31. Figure 4 Modified from: Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR. 2005;54(RR-16):1-31. Figure 5
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