AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 3
May 1991
HEPATITIS B VACCINE IN PREGNANCY: MATERNAL AND FETAL SAFETY Maurice Levy, M.D., and Gideon Koren, M.D.
ABSTRACT
The morbidity and mortality associated with hepatitis B virus (HBV) are considerable and while most infected persons recover completely, some will carry the virus for many years with increased risk of developing liver dysfunction, cirrhosis,1 or hepatocellular carcinoma.2-3 Most of the HBV infections are acquired very early in life45 and newborns of infected mothers are at greatest risk for developing chronic liver disease. Active immunization seems to be the most effective method available for prevention of HBV infection for both adults and children. Hepatitis B vaccine is recommended for pregnant women in endemic areas where the majority of the adult population have evidence of past or present infections. Due to passive transfer of maternal antibodies, vaccination of pregnant women will protect the neonate for an extended period. Although several studies have doc-
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
Perinatal transmission of hepatitis B (HB) virus occurs if the mother has had acute HB infection during late pregnancy or in the first months postpartum, or if the mother is a chronic HB antigen carrier. Vertical transmission from chronic carriers exceeds 90% and accounts for up to 40% of the world chronic carriers in endemic areas. Hepatitis in pregnancy is not associated with increased abortion rate, stillbirth, or congenital malformation. However, prematurity seems to be increased if hepatitis is acquired in the last trimester. Sixty percent of pregnant women who acquire acute HB infections at or near delivery will transmit the HB virus to their offspring. Although infection is rarely symptomatic, 70 to 90% of the babies will remain chronically infected into adult life and be prone to cirrhosis and hepatocellular carcinoma. Because of such high risks and the safety and efficacy (seroconversion 90 to 100%) of HB vaccine in preventing HB infection, it is recommended that HB vaccine be given to pregnant women at high risk. However, its safety to the fetus is not well documented. Only one human study reports the safety and efficacy of Heptavax, but only when administered (to 72 pregnant women) in the last trimester of pregnancy when embryopathy cannot occur. We report pregnancy outcome in ten women, mostly health care personnel or patients traveling to endemic areas exposed to the vaccine during the first trimester of pregnancy. No congenital abnormalities were observed and all the infants are physically and developmentally normal for their ages at 2 to 12 months. Although small, this cohort suggests safe use of the vaccine in early pregnancy. Many more cases will have to be collected in order to be able to rule out some risk of malformation above the 3% in the general population.
umented the efficacy and the safety of hepatitis B vaccine in adults, children, and infants,6"11 the safety to the fetus is not well documented. In this report we wish to review the benefits of the use of hepatitis B vaccine during pregnancy, and to review our experience in a prospective cohort of women counseled and followed up at the Motherisk program in Toronto. HEPATITIS B IN PREGNANCY AND PERINATAL TRANSMISSION
The maternal course of hepatitis B infection is generally unaltered by pregnancy. Although the virus crosses the placenta, fetal infection in utero is rare. Intrauterine HBV infection is not correlated with maternal hepatic dysfunction, maternal serum
Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Departments of Pediatrics and Pharmacology, University of Toronto, Toronto, Canada Reprint requests: Dr. Koren, Division of Clinical Pharmacology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8 Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
227
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 3
228
HB VACCINES
Currently, two types of vaccines are available, both containing a purified form of HBsAg that stimulates the production of protective surface antibodies (anti-HBs) in the recipient. Heptavax is derived from the plasma of hepatitis B carriers. The antigenic material is not derived from microorganisms propagated in the laboratory but directly from human material. The preparation procedure removes the nonsurface antigen of HBV, serum proteins, and other infectious agents that may have been present in the initial plasma pool. The second and relatively new type of vaccine, Recombivax is produced by employing recombinant DNA technology. It is prepared by culturing the yeast Sacharomyces cerevisiae containing a plasmid with the gene for HBsAg. The yeast cells produce HBsAg but not the virus or other viral antigens. The safety and efficacy of both vaccines is well documented.41-42 Seroconversion rates for anti HBS in vaccines range from 90 to 100% and protection conferred by the vaccine lasts for at least 5 years. Reported side effects in recipients of both types of vaccine have been mild, transient, and generally limited to soreness and redness of the injection site and low-grade fever (•
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May 1991
HEPATITIS B VACCINE IN PREGNANCY/Levy, Koren
Although the hepatitis B vaccine is safe for the patients, its safety to the fetus is not well documented. The fetal risk from perinatal transmission (vertical and horizontal) of HB V is real and therefore every effort should be made to detect pregnant women who are chronic carriers of HBsAg and also those who are at high risk of exposure. Such screening of pregnant women for HBsAg is now recommended by most authorities, and effort should be made, where routine screening is not implemented, to detect carriers in specific categories of pregnant women. In low endemic areas the cost effectiveness of a routine screening program for pregnant women is being debated. Hepatitis B can now be prevented by a safe and effective vaccine and individuals at risk should be offered active immunization. Acute exposure to infected blood should be treated by passive immunization. Neonatal transmission would be averted by both passive and active immunization. Protective antibodies induced by immunization in a pregnant woman are transferred across the placenta to the fetus and passively protect the newborn. In cases where such antibodies preexist, immunization during pregnancy can potentially increase the level of maternal antibodies that will cross the placenta and protect the neonate and the infant. The Nigerian study described the safety of Heptavax to the fetus45 but one has to consider that the vaccine was administered during the third trimester and not during embryogenesis. Our cohort is further supported by case reports affirming the safety of the vaccine when administered during the first trimester of pregnancy. Although the number is relatively small, such information may prevent women from aborting, as happened in our series. Because of obvious ethical considerations, it is impossible to execute prospective studies of use of HB vaccine in the first trimester of pregnancy. We have to rely on prospective collection of cases that occur accidentally with women having the vaccine. The Motherisk program is especially designed for prospective collection of such cases, including verification of time of exposure, other reproductive risk factors, and outcome. That none of our ten cases exhibited adverse fetal outcome suggests safe use of the vaccine in early pregnancy. However, many more cases will have to be collected in order to be able to prove that there is not even a slight risk above the + 3% in the general population.
3. Beasley RP, Hwang LW, Lin CC, Chien CS: Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan. Lancet 2:1129-1133, 1981 4. Blumberg BS, London WT: Hepatitis B virus and primary hepatocellular carcinoma: Relationship of ICRONS to cancer. In Essex M, Tedero G, zur Hausen H (eds): Viruses in Naturally Occurring Cancer. Conference on cell
5.
6.
7. 8.
9. 10.
11.
12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
REFERENCES
24. 25.
1. Viola LA, Barisson IG, Coleman JC, Fluker JL, Paradinas FJ, Evans BA: Natural history of liver disease in chronic hepatitis surface antigen carriers. Lancet 2:1156—1159, 1981 2. Beasley RP: Hepatitis B virus as the etiologic agent in hepatocellular carcinoma—epidemiologic considerations. Hepatology 2(Suppl):215-265, 1982
26. 27. 28.
proliferation, vol 7. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 1980, pp 401-421 Tong MJ, Thursby MW, Lin JH, Weissman JY, McPeak CM: Studies on the maternal infant transmission of hepatitis B virus and HBV infection within families. Prog Med Virol 27:137, 1981 Lo KJ, Lee SD, Tsai YT, Wu TC, Chan CY, Chen GH, Yeh CL: Long term immunogenicity and efficacy of hepatitis B vaccine in infants born to HBeAg positive HBsAgcarrier mothers. Hepatology 8:1647-1650, 1988 Pongpipat D, Suvatte V, Assateerwatts A: Vaccination against hepatitis B virus infections in neonates. Helv Paediatr Acta 39:231-236, 1984 Esteban JI, Genesca J, Esteban R, Hernandez JM, Seio JOG, Buti M, Money R, Guardia J: Immunoprophylaxis of perinatal transmission of the hepatitis B vaccine in a low prevalence area. J Med Virol 18:381-391, 1986 Ayoola EA: The immune response of healthy Nigerian adults to small dose of hepatitis B vaccine. Comparison of 10 and 20 ng doses. J Med Virol 12:223, 1984 Maupas P, Phiron JP, Goudeau A, Coursaget P, Perrin J, Baun F, Denis F, Dip-Mar I: Active immunization against Hepatitis B in an area of high endemicity. Part II. Prevention of early infection of the child. Prog Med Virol 27:188,1981 Szmuness W, Stevens CE, Harley EJ, Oleszko WR, William DC, Sadousky R, Morrisson JM, Kellner A: Hepatitis B vaccine: Demonstration of efficacy in a controlled clinical trial in a high risk population in the United States. N EnglJ Med 202:883, 1980 Lin HH, Ohto HT, et al: Studies on the risk factors of intrauterine infection of Hepatitis B virus. Acta Obstet Gynecol Jpn 37:2393-2400, 1985 Hwang LY, Roggendorf M, Beasley RP, et al: Perinatal transmission of Hepatitis B virus: Role of maternal HBeAg and and HBcAgIgM. J Med Virol 15:265-269, 1985 Zondeck B, Brombert YM: Infectious hepatitis in pregnancy. J M Sinai Hosp 14:222, 1947 Wahi PN, Arora MM: Epidemic hepatitis. N Engl J Med 248:451, 1953 Naidu SS, Viswanathan R: Infectious hepatitis in pregnancy during Delhi epidemic. India J Med Res 45(Suppl):71, 1957 Malkani PK, Grewal AK: Observations on infectious hepatitis in pregnancy. India J Med Res 45(Suppl):77, 1957 LongJS, Boysen H, Priest FO: Infectious hepatitis and pregnancy. Am J Obstet Gynecol 70:282, 1955 Frucht HL, Metcalfe J: Mortality and late results of infectious hepatitis in pregnant women. N EnglJ Med 251: 1094, 1954 Vincent CR: Jaundice in pregnancy. Obstet Gynecol 9:595, 1957 Dill LV: Acute yellow atrophy of liver associated with pregnancy: Review of literature and six cases. Obstet Gynecol Surv 5:139, 1950 Ingersley M, Teilum G: Jaundice during pregnancy. Acta Obstet Gynecol Scand 31:74, 1951 Roth LG: Infectious hepatitis in pregnancy. Am J Med Sci 225:139, 1953 Thorling L: Jaundice in pregnancy: Clinical study. Acta Med Scand (Suppl) 302:1, 1955 Peretz A, et al: Infectious hepatitis in pregnancy. Obstet Gynecol 14:435, 1959 Dennig Von H, Buckmann R: Virus hepatitis and pregnancy. Munch Med Wochenschr 103:1817, 1961 Cahill KM: Hepatitis in pregnancy. Surg Gynecol Obstet 114:545, 1962 Adams R, Combes B: Viral hepatitis during pregnancy. JAMA 192:95, 1965 231
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
DISCUSSION
29. Hieber JP, Dalton D, Shorey J, Combes B: Hepatitis and pregnancy. J Pediatr 91:545-549, 1977 30. Schweitzer IL, Funn AEG, Peters RL, et al: Viral hepatitis B in neonates and infants. Am J Med 55:762-771. 1973 31. Schwietzer IL, Mosley JW, Aschcavai M, et al: Factors influencing neonatal infection by hepatitis B virus. Gastroenterology 65:277-283, 1973 32. Gilbert GL: Vertical transmission of hepatitis B: Review of the literature and recommendation for management. Med J Aust 1:280-285, 1981 33. OkadaK, Kamiyamal, InomataM, etal: Antigen and anti-e in the serum of asymptomatic carrier mothers as indicator of the positive and negative transmission of hepatitis B virus to their infants. N Engl J Med 294:746-749, 1976 34. Ho-Hsiung L, Tee TY, Chen DS, et al: Transplacental leakage of HBeAg positive maternal blood as the most likely route in causing intrauterine infection with hepatitis B virus. J Pediatr 111:877-881, 1987 35. Editorial: Prevention of perinatally transmitted Hepatitis B virus infections. Lancet 1:939-942, 1984 36. Szmunes W, Stevens CE, Kew MC, et al: Baseline epidemiological studies for a hepatitis B vaccine trial in Kaugwane. S Afr Med J 64:891-893, 1983 37. Jonas MM, Schiff ER, O'Sullivan MJ, et al: Failure of centers for disease control criteria to identify hepatitis B infection in a large municipal obstetrical population. Ann Intern Med 107:335-337, 1987 38. Tada H, Yanagida M, Mishina J, et al: Combined passive and active immunization for preventing perinatal transmission of hepatitis B virus carrier state. Pediatrics 70:613-
232
May 1991
619, 1982 39. Beasley RP, Hwang Y, Lee GCY, et al: Prevention of perinatally transmitted hepatitis B virus infection with hepatitis B immunoglobulin and hepatitis B vaccine. Lancet 2:1099-1102, 1983 40. Wong VCW, Ip HMH, Reesnick HW, et al: Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis B vaccine and hepatitis B-immunoglobulin. Lancet 37:2393-2400, 1984 41. Fagan EA, Eddleston ALWF: Hepatitis vaccination. Clin Immunol Allergy 5:43-85, 1985 42. Jilg W, Deinhardt F: Results of immunization with a recombinant yeast derived hepatitis B vaccine. J Infect 13 (Suppl A):47-51, 1986 43. MMWR: Current trends. The safety of hepatitis B virus vaccine. MMWR 32:134-136, 1983 44. Riberta EF, Dukta AJ: Polyneuropathy associated with administration of hepatitis B vaccine (Retter). N Engl J Med 309:614-615, 1983 45. Ayoda EA, Johnson AOK: Hepatitis B in pregnancy: Immunogenicity, safety and transfer of antibodies to infants. Int J Gynecol Obstet 25:297-301, 1987 46. National Advisory Committee on Immunization: A Guide to Immunization for Canadians, Ottawa: Health and Welfare
Canada 47. Hepatitis B Vaccine, Drug Ther Bull 23:49-51, 1985 48. National Advisory Committee on Immunization. Statement on immunizing agents for the prevention of viral hepatitis, 13(22):99-106, 1987
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 3
May 1991
HEPATITIS B VACCINE IN PREGNANCY: MATERNAL AND FETAL SAFETY Maurice Levy, M.D., and Gideon Koren, M.D.
ABSTRACT
The morbidity and mortality associated with hepatitis B virus (HBV) are considerable and while most infected persons recover completely, some will carry the virus for many years with increased risk of developing liver dysfunction, cirrhosis,1 or hepatocellular carcinoma.2-3 Most of the HBV infections are acquired very early in life45 and newborns of infected mothers are at greatest risk for developing chronic liver disease. Active immunization seems to be the most effective method available for prevention of HBV infection for both adults and children. Hepatitis B vaccine is recommended for pregnant women in endemic areas where the majority of the adult population have evidence of past or present infections. Due to passive transfer of maternal antibodies, vaccination of pregnant women will protect the neonate for an extended period. Although several studies have doc-
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
Perinatal transmission of hepatitis B (HB) virus occurs if the mother has had acute HB infection during late pregnancy or in the first months postpartum, or if the mother is a chronic HB antigen carrier. Vertical transmission from chronic carriers exceeds 90% and accounts for up to 40% of the world chronic carriers in endemic areas. Hepatitis in pregnancy is not associated with increased abortion rate, stillbirth, or congenital malformation. However, prematurity seems to be increased if hepatitis is acquired in the last trimester. Sixty percent of pregnant women who acquire acute HB infections at or near delivery will transmit the HB virus to their offspring. Although infection is rarely symptomatic, 70 to 90% of the babies will remain chronically infected into adult life and be prone to cirrhosis and hepatocellular carcinoma. Because of such high risks and the safety and efficacy (seroconversion 90 to 100%) of HB vaccine in preventing HB infection, it is recommended that HB vaccine be given to pregnant women at high risk. However, its safety to the fetus is not well documented. Only one human study reports the safety and efficacy of Heptavax, but only when administered (to 72 pregnant women) in the last trimester of pregnancy when embryopathy cannot occur. We report pregnancy outcome in ten women, mostly health care personnel or patients traveling to endemic areas exposed to the vaccine during the first trimester of pregnancy. No congenital abnormalities were observed and all the infants are physically and developmentally normal for their ages at 2 to 12 months. Although small, this cohort suggests safe use of the vaccine in early pregnancy. Many more cases will have to be collected in order to be able to rule out some risk of malformation above the 3% in the general population.
umented the efficacy and the safety of hepatitis B vaccine in adults, children, and infants,6"11 the safety to the fetus is not well documented. In this report we wish to review the benefits of the use of hepatitis B vaccine during pregnancy, and to review our experience in a prospective cohort of women counseled and followed up at the Motherisk program in Toronto. HEPATITIS B IN PREGNANCY AND PERINATAL TRANSMISSION
The maternal course of hepatitis B infection is generally unaltered by pregnancy. Although the virus crosses the placenta, fetal infection in utero is rare. Intrauterine HBV infection is not correlated with maternal hepatic dysfunction, maternal serum
Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Departments of Pediatrics and Pharmacology, University of Toronto, Toronto, Canada Reprint requests: Dr. Koren, Division of Clinical Pharmacology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8 Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
227
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 3
228
HB VACCINES
Currently, two types of vaccines are available, both containing a purified form of HBsAg that stimulates the production of protective surface antibodies (anti-HBs) in the recipient. Heptavax is derived from the plasma of hepatitis B carriers. The antigenic material is not derived from microorganisms propagated in the laboratory but directly from human material. The preparation procedure removes the nonsurface antigen of HBV, serum proteins, and other infectious agents that may have been present in the initial plasma pool. The second and relatively new type of vaccine, Recombivax is produced by employing recombinant DNA technology. It is prepared by culturing the yeast Sacharomyces cerevisiae containing a plasmid with the gene for HBsAg. The yeast cells produce HBsAg but not the virus or other viral antigens. The safety and efficacy of both vaccines is well documented.41-42 Seroconversion rates for anti HBS in vaccines range from 90 to 100% and protection conferred by the vaccine lasts for at least 5 years. Reported side effects in recipients of both types of vaccine have been mild, transient, and generally limited to soreness and redness of the injection site and low-grade fever (•
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Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
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May 1991
HEPATITIS B VACCINE IN PREGNANCY/Levy, Koren
Although the hepatitis B vaccine is safe for the patients, its safety to the fetus is not well documented. The fetal risk from perinatal transmission (vertical and horizontal) of HB V is real and therefore every effort should be made to detect pregnant women who are chronic carriers of HBsAg and also those who are at high risk of exposure. Such screening of pregnant women for HBsAg is now recommended by most authorities, and effort should be made, where routine screening is not implemented, to detect carriers in specific categories of pregnant women. In low endemic areas the cost effectiveness of a routine screening program for pregnant women is being debated. Hepatitis B can now be prevented by a safe and effective vaccine and individuals at risk should be offered active immunization. Acute exposure to infected blood should be treated by passive immunization. Neonatal transmission would be averted by both passive and active immunization. Protective antibodies induced by immunization in a pregnant woman are transferred across the placenta to the fetus and passively protect the newborn. In cases where such antibodies preexist, immunization during pregnancy can potentially increase the level of maternal antibodies that will cross the placenta and protect the neonate and the infant. The Nigerian study described the safety of Heptavax to the fetus45 but one has to consider that the vaccine was administered during the third trimester and not during embryogenesis. Our cohort is further supported by case reports affirming the safety of the vaccine when administered during the first trimester of pregnancy. Although the number is relatively small, such information may prevent women from aborting, as happened in our series. Because of obvious ethical considerations, it is impossible to execute prospective studies of use of HB vaccine in the first trimester of pregnancy. We have to rely on prospective collection of cases that occur accidentally with women having the vaccine. The Motherisk program is especially designed for prospective collection of such cases, including verification of time of exposure, other reproductive risk factors, and outcome. That none of our ten cases exhibited adverse fetal outcome suggests safe use of the vaccine in early pregnancy. However, many more cases will have to be collected in order to be able to prove that there is not even a slight risk above the + 3% in the general population.
3. Beasley RP, Hwang LW, Lin CC, Chien CS: Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan. Lancet 2:1129-1133, 1981 4. Blumberg BS, London WT: Hepatitis B virus and primary hepatocellular carcinoma: Relationship of ICRONS to cancer. In Essex M, Tedero G, zur Hausen H (eds): Viruses in Naturally Occurring Cancer. Conference on cell
5.
6.
7. 8.
9. 10.
11.
12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
REFERENCES
24. 25.
1. Viola LA, Barisson IG, Coleman JC, Fluker JL, Paradinas FJ, Evans BA: Natural history of liver disease in chronic hepatitis surface antigen carriers. Lancet 2:1156—1159, 1981 2. Beasley RP: Hepatitis B virus as the etiologic agent in hepatocellular carcinoma—epidemiologic considerations. Hepatology 2(Suppl):215-265, 1982
26. 27. 28.
proliferation, vol 7. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 1980, pp 401-421 Tong MJ, Thursby MW, Lin JH, Weissman JY, McPeak CM: Studies on the maternal infant transmission of hepatitis B virus and HBV infection within families. Prog Med Virol 27:137, 1981 Lo KJ, Lee SD, Tsai YT, Wu TC, Chan CY, Chen GH, Yeh CL: Long term immunogenicity and efficacy of hepatitis B vaccine in infants born to HBeAg positive HBsAgcarrier mothers. Hepatology 8:1647-1650, 1988 Pongpipat D, Suvatte V, Assateerwatts A: Vaccination against hepatitis B virus infections in neonates. Helv Paediatr Acta 39:231-236, 1984 Esteban JI, Genesca J, Esteban R, Hernandez JM, Seio JOG, Buti M, Money R, Guardia J: Immunoprophylaxis of perinatal transmission of the hepatitis B vaccine in a low prevalence area. J Med Virol 18:381-391, 1986 Ayoola EA: The immune response of healthy Nigerian adults to small dose of hepatitis B vaccine. Comparison of 10 and 20 ng doses. J Med Virol 12:223, 1984 Maupas P, Phiron JP, Goudeau A, Coursaget P, Perrin J, Baun F, Denis F, Dip-Mar I: Active immunization against Hepatitis B in an area of high endemicity. Part II. Prevention of early infection of the child. Prog Med Virol 27:188,1981 Szmuness W, Stevens CE, Harley EJ, Oleszko WR, William DC, Sadousky R, Morrisson JM, Kellner A: Hepatitis B vaccine: Demonstration of efficacy in a controlled clinical trial in a high risk population in the United States. N EnglJ Med 202:883, 1980 Lin HH, Ohto HT, et al: Studies on the risk factors of intrauterine infection of Hepatitis B virus. Acta Obstet Gynecol Jpn 37:2393-2400, 1985 Hwang LY, Roggendorf M, Beasley RP, et al: Perinatal transmission of Hepatitis B virus: Role of maternal HBeAg and and HBcAgIgM. J Med Virol 15:265-269, 1985 Zondeck B, Brombert YM: Infectious hepatitis in pregnancy. J M Sinai Hosp 14:222, 1947 Wahi PN, Arora MM: Epidemic hepatitis. N Engl J Med 248:451, 1953 Naidu SS, Viswanathan R: Infectious hepatitis in pregnancy during Delhi epidemic. India J Med Res 45(Suppl):71, 1957 Malkani PK, Grewal AK: Observations on infectious hepatitis in pregnancy. India J Med Res 45(Suppl):77, 1957 LongJS, Boysen H, Priest FO: Infectious hepatitis and pregnancy. Am J Obstet Gynecol 70:282, 1955 Frucht HL, Metcalfe J: Mortality and late results of infectious hepatitis in pregnant women. N EnglJ Med 251: 1094, 1954 Vincent CR: Jaundice in pregnancy. Obstet Gynecol 9:595, 1957 Dill LV: Acute yellow atrophy of liver associated with pregnancy: Review of literature and six cases. Obstet Gynecol Surv 5:139, 1950 Ingersley M, Teilum G: Jaundice during pregnancy. Acta Obstet Gynecol Scand 31:74, 1951 Roth LG: Infectious hepatitis in pregnancy. Am J Med Sci 225:139, 1953 Thorling L: Jaundice in pregnancy: Clinical study. Acta Med Scand (Suppl) 302:1, 1955 Peretz A, et al: Infectious hepatitis in pregnancy. Obstet Gynecol 14:435, 1959 Dennig Von H, Buckmann R: Virus hepatitis and pregnancy. Munch Med Wochenschr 103:1817, 1961 Cahill KM: Hepatitis in pregnancy. Surg Gynecol Obstet 114:545, 1962 Adams R, Combes B: Viral hepatitis during pregnancy. JAMA 192:95, 1965 231
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
DISCUSSION
29. Hieber JP, Dalton D, Shorey J, Combes B: Hepatitis and pregnancy. J Pediatr 91:545-549, 1977 30. Schweitzer IL, Funn AEG, Peters RL, et al: Viral hepatitis B in neonates and infants. Am J Med 55:762-771. 1973 31. Schwietzer IL, Mosley JW, Aschcavai M, et al: Factors influencing neonatal infection by hepatitis B virus. Gastroenterology 65:277-283, 1973 32. Gilbert GL: Vertical transmission of hepatitis B: Review of the literature and recommendation for management. Med J Aust 1:280-285, 1981 33. OkadaK, Kamiyamal, InomataM, etal: Antigen and anti-e in the serum of asymptomatic carrier mothers as indicator of the positive and negative transmission of hepatitis B virus to their infants. N Engl J Med 294:746-749, 1976 34. Ho-Hsiung L, Tee TY, Chen DS, et al: Transplacental leakage of HBeAg positive maternal blood as the most likely route in causing intrauterine infection with hepatitis B virus. J Pediatr 111:877-881, 1987 35. Editorial: Prevention of perinatally transmitted Hepatitis B virus infections. Lancet 1:939-942, 1984 36. Szmunes W, Stevens CE, Kew MC, et al: Baseline epidemiological studies for a hepatitis B vaccine trial in Kaugwane. S Afr Med J 64:891-893, 1983 37. Jonas MM, Schiff ER, O'Sullivan MJ, et al: Failure of centers for disease control criteria to identify hepatitis B infection in a large municipal obstetrical population. Ann Intern Med 107:335-337, 1987 38. Tada H, Yanagida M, Mishina J, et al: Combined passive and active immunization for preventing perinatal transmission of hepatitis B virus carrier state. Pediatrics 70:613-
232
May 1991
619, 1982 39. Beasley RP, Hwang Y, Lee GCY, et al: Prevention of perinatally transmitted hepatitis B virus infection with hepatitis B immunoglobulin and hepatitis B vaccine. Lancet 2:1099-1102, 1983 40. Wong VCW, Ip HMH, Reesnick HW, et al: Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis B vaccine and hepatitis B-immunoglobulin. Lancet 37:2393-2400, 1984 41. Fagan EA, Eddleston ALWF: Hepatitis vaccination. Clin Immunol Allergy 5:43-85, 1985 42. Jilg W, Deinhardt F: Results of immunization with a recombinant yeast derived hepatitis B vaccine. J Infect 13 (Suppl A):47-51, 1986 43. MMWR: Current trends. The safety of hepatitis B virus vaccine. MMWR 32:134-136, 1983 44. Riberta EF, Dukta AJ: Polyneuropathy associated with administration of hepatitis B vaccine (Retter). N Engl J Med 309:614-615, 1983 45. Ayoda EA, Johnson AOK: Hepatitis B in pregnancy: Immunogenicity, safety and transfer of antibodies to infants. Int J Gynecol Obstet 25:297-301, 1987 46. National Advisory Committee on Immunization: A Guide to Immunization for Canadians, Ottawa: Health and Welfare
Canada 47. Hepatitis B Vaccine, Drug Ther Bull 23:49-51, 1985 48. National Advisory Committee on Immunization. Statement on immunizing agents for the prevention of viral hepatitis, 13(22):99-106, 1987
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 3
