(Acta Paediatr Jpn 1992; 34: 656
N
659)
Prevention of Perinatal Transmission of Hepatitis B Virus Carrier State
’
’
Hiroshi Tada, M.D.’ Naoki Uga, M.D. , Yozen Fuse, M.D. , Mitsumasa Shimizu, M.D. Yuko Nemoto, M.D. , Eriko Wakae, M.D. , Yurino Okamoto, M.D. , Jun Mishina, M.D.* and Kiyoshi Baba, B.S.2
’,
e 2 ,
’
’
’
Department of Neonatology, Toho University School of Medicine and Tokyo Metropolitan Tsukiji Maternity Hospital, Tokyo, Japan
By means of passive and active immunization with hepatitis B immunoglobulin and hepatitis B vaccine, 396 of 407 babies born to hepatitis B antigen-positive carrier mothers, were protected from establishing the hepatitis B virus (HBV) carrier state during a follow-up period of 12 months or longer. Four infants developed the HBV carrier state before the completion of the immunoprophylaxis schedule, and another seven developed the state after the completion of the schedule. Seroconversion of anti-HBc was observed in 26.8% of the successfully protected infants. In Japan a nationwide program to prevent the vertical transmission of HBV with these procedures was established in 1986, and so liver diseases due to HBV are expected to be eliminated in the near future. Key Words Hepatitis B virus, Perinatal infection, Prevention of HBV, HBIC, H B vaccine
introduction In areas such as Asia and Oceania, where infection with hepatitis B virus (HBV) is endemic, the carrier state is transmitted from mothers to their babies [ 1,2], especially from those who are seropositive for hepatitis B antigen (HBeAg) [31. This type of transmission accounts for a substantial proportion of persistent infections with HBV. Babies can later develop hepatic diseases such as hepatocellular carcinoma, and serve as a reservoir of HBV for a further spread of infection in the community. The prevention Received August 14, 1992 Correspondence address: Hiroshi Tada, M.D., Department of Neonatology, Toho University School of Medicine, 6-1 1-1 Ohmori-nishi, Ohtaku, Tokyo, Japan.
of perinatal infection with HBV, therefore, is a matter of urgent concern in these areas [4-61. We have previously reported the protection of nine out of ten babies born to HBeAg’ mothers by the combined use of hepatitis B immunoglobulin (HBIG) and hepatitis B (HB) vaccine [4]. Our experience has now extended to 435 infants who were treated with this or a slightly modified protocol, and 407 of these have been followed for more than 1 year. Our results will be reported here.
Subjects and Methods Subjects The 435 infants born to mothers positive for HB surface antigen (HBsAg) and HBeAg received passive and active immunization with HBIG and HB vaccine. HBIG (Cohn’s fraction
Prevention of perinatal transmission of HBV (79) 657 11) with a titer for antibody to HBsAg (anti-HBs)
higher than 200 IU/ml and F(ab'), fragments prepared by pepsin digestion were provided by the Japanese Red Cross Central Blood Center, Tokyo. Plasma-derived HB vaccine (Kitasato Institute, Tokyo) or yeast-recombinant HB vaccine (Merck Sharp & Dohme Research Laboratories, USA) was injected subcutaneously.
Laboratory method Levels of HBsAg and anti-HBs were measured by reversed passive hemagglutination (RPHA) and passive hemagglutination (PHA). Levels of HBeAg and its antibody (anti-HBe) were determined by an immunodiffusion method or an enzyme immunoassay (EIA). The level of antibody to hepatitis B core antigen (anti-HBc) was measured by the immunoadherence hemagglutination method or EIA. HBV-specific DNA polymerase activity was measured by the modified method of Kaplan et a1 [7]. Combined passive and active immunization Once the absence of HBsAg in the cord blood of the neonates born to HBeAg carrier mothers was confirmed by RPHA, 200IU of F(ab'), fragments of HBIG were administered intravenousiy, usually within 2 hr of delivery. After 24 hr the neonates were given an injection of 200 IU of intact HBIG intramuscularly provided that they could keep anti-HBs in the circulation, as detected by PHA during the period. Since then, HBsAg, anti-HBs, glutamate oxaloacetate transaminase and glutamic-pyruvic transaminase have been checked every month. When the serum level of anti-HBs decreased to less than Z3, an additional dose of HBIG (200IU) was +
HB Vaccine
i
i
2
3
1
HBIG
b
1
4
given intramuscularly, usually at 2 months of age. Between 1 week and 3 months of birth (in many cases at 1 or 2 months), the infants were inoculated with HB vaccine (5-10 pg) subcutaneously. They received the second vaccine 1 month later and the third vaccine 3 months after the first vaccination. If necessary, the fourth or an additional vaccine were given thereafter (Fig. 1). The previous protocol we reported [4] was slightly modified. Plasma-derived HB vaccine without alum adjuvant was given to the first 85 infants and the vaccine with alum was given to 24 1 infants. The recombinant-yeast HB vaccine was given to the most recent 76 infants. In 107 infants, only intramuscular injection of HBIG was given soon after birth without F(ab'),. No untoward reactions for HBIG or vaccines were observed throughout our practice over 12 years.
Results By means of passive and active immunization, 396 of 407 babies born to HBeAg' carrier mothers were protected from developing the HBV carrier state during a follow-up period of 12 months or longer (Fig. 2). It took 5-6 months to complete the schedule of passive and active immunization. Six babies showed HBs antigenemia before the end of the immunization schedule. In four babies, HBsAg was detected 24, 32, 61 and 89 days after birth and remained positive for more than 12 months. The cord blood and blood sample taken 1 , 2 and 5 days after birth were HBsAg-, as determined by RPHA. One baby showed HBs antigenemia at 7 days after birth, but this disappeared at 12
5
6
7
Time (months after birth) Fig. 1: Schedule of prevention for the vertical transmission of HBV.
Vol. 34 No. 6 December 1992
8' 6J -
658 (80) Tada et al. Table 1 . The pattern of changes in serum HBc antibody in infants immunized with HBIG and HB vaccine
I
435 (HRs Ag I
(t)on cwd
blood)
(HRr Ag (-)
MI
cwd blood)
I
HBc antibody
i-I--;
407
(to~~oved mwe than
0
28
12 months) (fo~towedless than 12 months)
12 24 (months)
(+) +(-)+ ( + ) --.(+)+
I
( + I +(-I-
(-1 (+) (+)
Methods of HBIG injection IV + IM
IM
173 (77.6%) 18 (8.1%) 32 (14.3%)
35 (58.3%) 13(21.7%) 12 (20.0%)
IV, intravenous; IM, intramuscular.
Fig. 2: The result of prevention of vertical transmission of HBV (infants of HBe mothers). +
months and anti-HBs became detectable at 13 months. Seven infants developed HBs antigenemia after the completion of the immunization schedule. In these infants, HBsAg was first detected between 12 and 22 months. Six of them were anti-HBs - even after they received between two and eight doses of vaccine. In one baby it appeared that anti-HBs developed by vaccination was overwhelmed by HBsAg at 15 months after birth. In general, HBsAg-associated DNA polymerase activity was higher in the sera of mothers whose babies became HBsAg than those whose babies were protected. but the difference was not significant. In 283 infants who were followed for more than 24 months without detectable HBsAg, an increase in the titer of anti-HBc was detected in 75, thereby indicating that they contracted a transient infection of HBV (Table 1). Accordingly, the cumulative incidence of persistent and transient infection in babies born to HBeAg mothers and receiving immunoprophylaxis was estimated to be 2 1.1%. +
+
Discussion Perinatal infection of HBV is very frequent in neonates born to HBeAg' mothers, of whom
approximately 85% establish a carrier state of HBV [4]. Some of these later develop hepatitis, liver cirrhosis and primary hepatocellular carcinoma themselves [8]. The prevention of perinatal transmission from HBeAg' mothers to their babies, therefore, deserves top priority for the use of HB vaccine. In 1982 we reported protecting nine out of ten babies born to HBeAg' mothers from developing an HBV carrier state by combined passive and active immunization [4]. Including these babies, a total of 435 cases have been treated by the same or a slightly modified protocol, 407 of which were followed for more than 12 months. There were no significant differences in the protective efficacy of three types of vaccine, but the infants vaccinated with recombinant vaccine required fewer injections of vaccine to achieve active immunization. Our success in protecting as many as 396 (98.6%) of 407 infants at high risk demonstrates a high efficacy of the methods employed. Eleven infants developed the HBV carrier state. Four of these developed HBs antigenemia within 2 months of birth. There may be two possibilities for the infection of these babies. One is intra-uterine infection despite the fact that HBsAg was not detectable in cord blood by RPHA. The other is the failure to protect babies by HBIG administered after birth. In order to obtain an immediate protective level of antiHBs, F(ab'), fragments of HBIG, prepared with pepsin digestion, were administered intravenously, but apparently this was not enough to prevent infection when a high dose of HBV was received. Seven of these babies showed HBs antigenemia between 12 and 22 months of birth. As six of them tested negative to anti-HBs by the
Acta Paediatr Jpn
Prevention ofperinatal transmission of HBV (8 1) 659 PHA method, they might have been low responders to the HB vaccine used. After completion of our immunoprophylaxis schedule, one infant became an HBV carrier. He remained positive for anti-HBs up to 12 months after birth, possibly due to active immunization, but HBsAg became detectable in the serum at 15 months. This suggeststhat a horizontal infection could occur despite immunoprophylaxis if the anti-HBs response to HB vaccine is weak. We also observed some cases who had become anti-HBc even after 2 years of age. Therefore it might be necessary to maintain serum antibody levels for at least 3 years after birth. Since 1986 a nationwide program of prevention of vertical transmission of HBV has been established in Japan. At present, 1.2 million babies are born annually in Japan, and if immunization is not performed, approximately 50,000 infants may become HBV carriers. By protecting these infants against vertical transmission, the prevalence of HBV carriers decreases below 5%. We expect that within a couple of generations, liver diseases due to HBV may be eliminated in Japan.
References 1. Mazzur S, Blumberg BS, Friedaender JS. Silent
maternal transmission of Australia antigen. Nature 1974; 247: 41-43. 2. Stevens CE, Beasley RP, Tsui J et al. Vertical
3.
4.
+
Vol. 34 No. 6 December 1992
5.
6.
7.
transmission of hepatitis B antigen in Taiwan. N Engl J Med 1975; 292: 171-774. Okada K, Kamiyama I, Inomata M et al. E antigen and antis in the serum of asymptomatic carrier mothers as indicators of hepatitis B virus to their infants. N Engl J Med 1976; 294: 746-749. Tada H, Yanagida M, Mishina J et al. Combined passive and active immunization for preventing perinatal transmission of Hepatitis B virus carrier state. Pediatrics 1982; 70: 6 13-6 19. Beasley RP, Hwang LY, Lee GC-Y et al. Prevention of perinatally transmitted hepatitis B virus infection with hepatitis B immunoglobulin and hepatitis B vaccine. Lancet 1983; 2: 1099-1 102. Wong VCM, Ip HMH, Reasink HW et al. Prevention of HBsAg camer state in newborn infants of mothers who are chronic carriers of HBsAg by administration of hepatitis B vaccine and hepatitis B immunoglobulin. Lancet 1984; 1: 921-926. Kaplan PM, Greenman RL et al. DNA polymerase associated with human hepatitis B antigen. J Virol 1973; 12: 995-1005.
8. Ohbayashi A, Okochi K, Mayumi M. Familial cluster of asymptomatic carriers of Australia antigen and patients with chronic liver disease or primary liver cancer. Gastroenterology 1972; 62: 618-625.
N
659)
Prevention of Perinatal Transmission of Hepatitis B Virus Carrier State
’
’
Hiroshi Tada, M.D.’ Naoki Uga, M.D. , Yozen Fuse, M.D. , Mitsumasa Shimizu, M.D. Yuko Nemoto, M.D. , Eriko Wakae, M.D. , Yurino Okamoto, M.D. , Jun Mishina, M.D.* and Kiyoshi Baba, B.S.2
’,
e 2 ,
’
’
’
Department of Neonatology, Toho University School of Medicine and Tokyo Metropolitan Tsukiji Maternity Hospital, Tokyo, Japan
By means of passive and active immunization with hepatitis B immunoglobulin and hepatitis B vaccine, 396 of 407 babies born to hepatitis B antigen-positive carrier mothers, were protected from establishing the hepatitis B virus (HBV) carrier state during a follow-up period of 12 months or longer. Four infants developed the HBV carrier state before the completion of the immunoprophylaxis schedule, and another seven developed the state after the completion of the schedule. Seroconversion of anti-HBc was observed in 26.8% of the successfully protected infants. In Japan a nationwide program to prevent the vertical transmission of HBV with these procedures was established in 1986, and so liver diseases due to HBV are expected to be eliminated in the near future. Key Words Hepatitis B virus, Perinatal infection, Prevention of HBV, HBIC, H B vaccine
introduction In areas such as Asia and Oceania, where infection with hepatitis B virus (HBV) is endemic, the carrier state is transmitted from mothers to their babies [ 1,2], especially from those who are seropositive for hepatitis B antigen (HBeAg) [31. This type of transmission accounts for a substantial proportion of persistent infections with HBV. Babies can later develop hepatic diseases such as hepatocellular carcinoma, and serve as a reservoir of HBV for a further spread of infection in the community. The prevention Received August 14, 1992 Correspondence address: Hiroshi Tada, M.D., Department of Neonatology, Toho University School of Medicine, 6-1 1-1 Ohmori-nishi, Ohtaku, Tokyo, Japan.
of perinatal infection with HBV, therefore, is a matter of urgent concern in these areas [4-61. We have previously reported the protection of nine out of ten babies born to HBeAg’ mothers by the combined use of hepatitis B immunoglobulin (HBIG) and hepatitis B (HB) vaccine [4]. Our experience has now extended to 435 infants who were treated with this or a slightly modified protocol, and 407 of these have been followed for more than 1 year. Our results will be reported here.
Subjects and Methods Subjects The 435 infants born to mothers positive for HB surface antigen (HBsAg) and HBeAg received passive and active immunization with HBIG and HB vaccine. HBIG (Cohn’s fraction
Prevention of perinatal transmission of HBV (79) 657 11) with a titer for antibody to HBsAg (anti-HBs)
higher than 200 IU/ml and F(ab'), fragments prepared by pepsin digestion were provided by the Japanese Red Cross Central Blood Center, Tokyo. Plasma-derived HB vaccine (Kitasato Institute, Tokyo) or yeast-recombinant HB vaccine (Merck Sharp & Dohme Research Laboratories, USA) was injected subcutaneously.
Laboratory method Levels of HBsAg and anti-HBs were measured by reversed passive hemagglutination (RPHA) and passive hemagglutination (PHA). Levels of HBeAg and its antibody (anti-HBe) were determined by an immunodiffusion method or an enzyme immunoassay (EIA). The level of antibody to hepatitis B core antigen (anti-HBc) was measured by the immunoadherence hemagglutination method or EIA. HBV-specific DNA polymerase activity was measured by the modified method of Kaplan et a1 [7]. Combined passive and active immunization Once the absence of HBsAg in the cord blood of the neonates born to HBeAg carrier mothers was confirmed by RPHA, 200IU of F(ab'), fragments of HBIG were administered intravenousiy, usually within 2 hr of delivery. After 24 hr the neonates were given an injection of 200 IU of intact HBIG intramuscularly provided that they could keep anti-HBs in the circulation, as detected by PHA during the period. Since then, HBsAg, anti-HBs, glutamate oxaloacetate transaminase and glutamic-pyruvic transaminase have been checked every month. When the serum level of anti-HBs decreased to less than Z3, an additional dose of HBIG (200IU) was +
HB Vaccine
i
i
2
3
1
HBIG
b
1
4
given intramuscularly, usually at 2 months of age. Between 1 week and 3 months of birth (in many cases at 1 or 2 months), the infants were inoculated with HB vaccine (5-10 pg) subcutaneously. They received the second vaccine 1 month later and the third vaccine 3 months after the first vaccination. If necessary, the fourth or an additional vaccine were given thereafter (Fig. 1). The previous protocol we reported [4] was slightly modified. Plasma-derived HB vaccine without alum adjuvant was given to the first 85 infants and the vaccine with alum was given to 24 1 infants. The recombinant-yeast HB vaccine was given to the most recent 76 infants. In 107 infants, only intramuscular injection of HBIG was given soon after birth without F(ab'),. No untoward reactions for HBIG or vaccines were observed throughout our practice over 12 years.
Results By means of passive and active immunization, 396 of 407 babies born to HBeAg' carrier mothers were protected from developing the HBV carrier state during a follow-up period of 12 months or longer (Fig. 2). It took 5-6 months to complete the schedule of passive and active immunization. Six babies showed HBs antigenemia before the end of the immunization schedule. In four babies, HBsAg was detected 24, 32, 61 and 89 days after birth and remained positive for more than 12 months. The cord blood and blood sample taken 1 , 2 and 5 days after birth were HBsAg-, as determined by RPHA. One baby showed HBs antigenemia at 7 days after birth, but this disappeared at 12
5
6
7
Time (months after birth) Fig. 1: Schedule of prevention for the vertical transmission of HBV.
Vol. 34 No. 6 December 1992
8' 6J -
658 (80) Tada et al. Table 1 . The pattern of changes in serum HBc antibody in infants immunized with HBIG and HB vaccine
I
435 (HRs Ag I
(t)on cwd
blood)
(HRr Ag (-)
MI
cwd blood)
I
HBc antibody
i-I--;
407
(to~~oved mwe than
0
28
12 months) (fo~towedless than 12 months)
12 24 (months)
(+) +(-)+ ( + ) --.(+)+
I
( + I +(-I-
(-1 (+) (+)
Methods of HBIG injection IV + IM
IM
173 (77.6%) 18 (8.1%) 32 (14.3%)
35 (58.3%) 13(21.7%) 12 (20.0%)
IV, intravenous; IM, intramuscular.
Fig. 2: The result of prevention of vertical transmission of HBV (infants of HBe mothers). +
months and anti-HBs became detectable at 13 months. Seven infants developed HBs antigenemia after the completion of the immunization schedule. In these infants, HBsAg was first detected between 12 and 22 months. Six of them were anti-HBs - even after they received between two and eight doses of vaccine. In one baby it appeared that anti-HBs developed by vaccination was overwhelmed by HBsAg at 15 months after birth. In general, HBsAg-associated DNA polymerase activity was higher in the sera of mothers whose babies became HBsAg than those whose babies were protected. but the difference was not significant. In 283 infants who were followed for more than 24 months without detectable HBsAg, an increase in the titer of anti-HBc was detected in 75, thereby indicating that they contracted a transient infection of HBV (Table 1). Accordingly, the cumulative incidence of persistent and transient infection in babies born to HBeAg mothers and receiving immunoprophylaxis was estimated to be 2 1.1%. +
+
Discussion Perinatal infection of HBV is very frequent in neonates born to HBeAg' mothers, of whom
approximately 85% establish a carrier state of HBV [4]. Some of these later develop hepatitis, liver cirrhosis and primary hepatocellular carcinoma themselves [8]. The prevention of perinatal transmission from HBeAg' mothers to their babies, therefore, deserves top priority for the use of HB vaccine. In 1982 we reported protecting nine out of ten babies born to HBeAg' mothers from developing an HBV carrier state by combined passive and active immunization [4]. Including these babies, a total of 435 cases have been treated by the same or a slightly modified protocol, 407 of which were followed for more than 12 months. There were no significant differences in the protective efficacy of three types of vaccine, but the infants vaccinated with recombinant vaccine required fewer injections of vaccine to achieve active immunization. Our success in protecting as many as 396 (98.6%) of 407 infants at high risk demonstrates a high efficacy of the methods employed. Eleven infants developed the HBV carrier state. Four of these developed HBs antigenemia within 2 months of birth. There may be two possibilities for the infection of these babies. One is intra-uterine infection despite the fact that HBsAg was not detectable in cord blood by RPHA. The other is the failure to protect babies by HBIG administered after birth. In order to obtain an immediate protective level of antiHBs, F(ab'), fragments of HBIG, prepared with pepsin digestion, were administered intravenously, but apparently this was not enough to prevent infection when a high dose of HBV was received. Seven of these babies showed HBs antigenemia between 12 and 22 months of birth. As six of them tested negative to anti-HBs by the
Acta Paediatr Jpn
Prevention ofperinatal transmission of HBV (8 1) 659 PHA method, they might have been low responders to the HB vaccine used. After completion of our immunoprophylaxis schedule, one infant became an HBV carrier. He remained positive for anti-HBs up to 12 months after birth, possibly due to active immunization, but HBsAg became detectable in the serum at 15 months. This suggeststhat a horizontal infection could occur despite immunoprophylaxis if the anti-HBs response to HB vaccine is weak. We also observed some cases who had become anti-HBc even after 2 years of age. Therefore it might be necessary to maintain serum antibody levels for at least 3 years after birth. Since 1986 a nationwide program of prevention of vertical transmission of HBV has been established in Japan. At present, 1.2 million babies are born annually in Japan, and if immunization is not performed, approximately 50,000 infants may become HBV carriers. By protecting these infants against vertical transmission, the prevalence of HBV carriers decreases below 5%. We expect that within a couple of generations, liver diseases due to HBV may be eliminated in Japan.
References 1. Mazzur S, Blumberg BS, Friedaender JS. Silent
maternal transmission of Australia antigen. Nature 1974; 247: 41-43. 2. Stevens CE, Beasley RP, Tsui J et al. Vertical
3.
4.
+
Vol. 34 No. 6 December 1992
5.
6.
7.
transmission of hepatitis B antigen in Taiwan. N Engl J Med 1975; 292: 171-774. Okada K, Kamiyama I, Inomata M et al. E antigen and antis in the serum of asymptomatic carrier mothers as indicators of hepatitis B virus to their infants. N Engl J Med 1976; 294: 746-749. Tada H, Yanagida M, Mishina J et al. Combined passive and active immunization for preventing perinatal transmission of Hepatitis B virus carrier state. Pediatrics 1982; 70: 6 13-6 19. Beasley RP, Hwang LY, Lee GC-Y et al. Prevention of perinatally transmitted hepatitis B virus infection with hepatitis B immunoglobulin and hepatitis B vaccine. Lancet 1983; 2: 1099-1 102. Wong VCM, Ip HMH, Reasink HW et al. Prevention of HBsAg camer state in newborn infants of mothers who are chronic carriers of HBsAg by administration of hepatitis B vaccine and hepatitis B immunoglobulin. Lancet 1984; 1: 921-926. Kaplan PM, Greenman RL et al. DNA polymerase associated with human hepatitis B antigen. J Virol 1973; 12: 995-1005.
8. Ohbayashi A, Okochi K, Mayumi M. Familial cluster of asymptomatic carriers of Australia antigen and patients with chronic liver disease or primary liver cancer. Gastroenterology 1972; 62: 618-625.
