乙肝免疫球蛋白阻断乙肝病毒母婴传播的研究
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摘要
目的：探讨乙型肝炎表面抗原(HBsAg)携带者孕妇及其新生儿应用乙肝免疫球蛋白(HBIG)对阻断乙肝母婴传播的效果，研究乙型肝炎病毒宫内传播的影响因素及临床预测指标，并探讨HBsAg携带者的母乳喂养问题。
方法：选取2001年3月至2003年3月在暨南大学第一附属医院系统产检分娩的HBsAg阳性产妇134例。分为HBIG组66例(A组)，非HBIG组68例(B组)，另取17例乙肝两对半和乙肝病毒DNA(HBV-DNA)全阴者为对照组C组。A组孕妇自孕28周起注射HBIG 200 IU，每4周一次至分娩；B组仅常规产前检查及监护。产后新生儿分为3组，Ⅰ、Ⅱ组应用HBIG和乙肝疫苗(HBVac)，Ⅲ组只注射HBVac，全部孕妇和新生儿定期测乙肝两对半和HBV-DNA。
结果：1 A、B两组新生儿出生24小时内外周血HBsAg阳性率比较，A组较B组明显降低，P＜0.05。
2 A、B、C三组新生儿出生时体重、身长、1分钟Apgar评分、新生儿黄疸、先天畸形、性别、合并其他内外科疾病两两比较均无显著性差异，P＞0.05。
3 A、B、C三组孕妇的产后出血、切口感染、宫内感染率两两比较均无显著性差异，P＞0.05。
4 A、B两组孕妇初乳HBsAg阳性率比较无显著性差异，P＞0.05。A、B两组孕妇初乳HBsAg阳性率分别与母亲血HBeAg比较，均有统计学意义，P＜0.05。
5 Ⅰ、Ⅱ、Ⅲ组新生儿6月龄HBsAb阳性率比较，Ⅰ组与Ⅱ组比较无显著性差异，P＞0.05；Ⅰ组与Ⅲ组比较，Ⅰ组较Ⅲ组明显升高，P＜0.05；Ⅱ组与Ⅲ组比较无显著性差异，P＞0.05。
6 婴儿6月龄人工喂养与母乳喂养产生HBsAb阳性率无显著性差异，P＞0.05。
结论：HBsAg携带者孕妇孕28周起每月注射HBIG及其新生儿联合应用HBIG及HBVac免疫，可以有效降低新生儿外周血HBsAg阳性率。
Objective: To explore the preventive effect of mathernofatal Hepatitis B virus(HBV) transmission after pregnant women earring HBsAg and their newborns have been passive immunized Hepatitis B immunoglobulin (HBIG), and to study the factors influencing HBV mtrauterine transmission and clinical predicable indexes, and to discuss the breast-feeding problem of pregnant women earring HBsAg.
Methods: 134 pregnant women caning HBsAg were choosen and divided into two groups: Groups A (n=66), which HBIG 200 IU was given monthly in late pregnancy; Group B (n=68), which abtained only common antenatal care. In addition, Pregnant women showing neither Hepatitis B virus immunological markers nor HBV-DNA were choosen as control group(group C, n=17). The newborns were also divided into three Groups: Group I and Group II abtained both HBIG and HBVac, and Group III abtained HBVac only. All the pregnant women and their newborns underwent an examination of HBV immunological markers and HBV-DNA at regular intervals.
Results: 1 The positive rate of HBsAg of newborns (age=24h) in Group A was significantly lower than that in Group B.
2 The newborn's birth weigh, height, one-minute Apgar scores, neonatal jaundice, congenital malformation, sex and other combinations had no significant difference among Group I , Group II and Group III.
3 The incidence of postpartum hemorrhage, incisional infection, intrauterine infection had no significant difference among three groups.
4 The HBsAg positive rate in colostrums of Group A and that of Group B had no significant difference. The HBsAg positive rate in colostrums of subjects in Group A and B correlated positively to the HBeAg positive rate of materal blood, respectively.
5 As the infants were 6 months old, the positive rate of HBsAb was similar between Group I and Group II, The HBsAb positive rate of infants was signicantly higher in Group I than in Group III, there was not significant difference between Group II and Group III.
6 As the infants were 6 months old, the HBeAb positive rate infant blood had no significant difference between breast-feeding and artificial-feeding.
Conclusions: The pregnant women earring HBsAg should be given HBIG monthly during late pregnancy, offsprings should abtained HBIG and recombiant HBVac, these procedures can effectively reduce the positive rate of HBsAg of newborns.
方法：选取2001年3月至2003年3月在暨南大学第一附属医院系统产检分娩的HBsAg阳性产妇134例。分为HBIG组66例(A组)，非HBIG组68例(B组)，另取17例乙肝两对半和乙肝病毒DNA(HBV-DNA)全阴者为对照组C组。A组孕妇自孕28周起注射HBIG 200 IU，每4周一次至分娩；B组仅常规产前检查及监护。产后新生儿分为3组，Ⅰ、Ⅱ组应用HBIG和乙肝疫苗(HBVac)，Ⅲ组只注射HBVac，全部孕妇和新生儿定期测乙肝两对半和HBV-DNA。
结果：1 A、B两组新生儿出生24小时内外周血HBsAg阳性率比较，A组较B组明显降低，P＜0.05。
2 A、B、C三组新生儿出生时体重、身长、1分钟Apgar评分、新生儿黄疸、先天畸形、性别、合并其他内外科疾病两两比较均无显著性差异，P＞0.05。
3 A、B、C三组孕妇的产后出血、切口感染、宫内感染率两两比较均无显著性差异，P＞0.05。
4 A、B两组孕妇初乳HBsAg阳性率比较无显著性差异，P＞0.05。A、B两组孕妇初乳HBsAg阳性率分别与母亲血HBeAg比较，均有统计学意义，P＜0.05。
5 Ⅰ、Ⅱ、Ⅲ组新生儿6月龄HBsAb阳性率比较，Ⅰ组与Ⅱ组比较无显著性差异，P＞0.05；Ⅰ组与Ⅲ组比较，Ⅰ组较Ⅲ组明显升高，P＜0.05；Ⅱ组与Ⅲ组比较无显著性差异，P＞0.05。
6 婴儿6月龄人工喂养与母乳喂养产生HBsAb阳性率无显著性差异，P＞0.05。
结论：HBsAg携带者孕妇孕28周起每月注射HBIG及其新生儿联合应用HBIG及HBVac免疫，可以有效降低新生儿外周血HBsAg阳性率。
Objective: To explore the preventive effect of mathernofatal Hepatitis B virus(HBV) transmission after pregnant women earring HBsAg and their newborns have been passive immunized Hepatitis B immunoglobulin (HBIG), and to study the factors influencing HBV mtrauterine transmission and clinical predicable indexes, and to discuss the breast-feeding problem of pregnant women earring HBsAg.
Methods: 134 pregnant women caning HBsAg were choosen and divided into two groups: Groups A (n=66), which HBIG 200 IU was given monthly in late pregnancy; Group B (n=68), which abtained only common antenatal care. In addition, Pregnant women showing neither Hepatitis B virus immunological markers nor HBV-DNA were choosen as control group(group C, n=17). The newborns were also divided into three Groups: Group I and Group II abtained both HBIG and HBVac, and Group III abtained HBVac only. All the pregnant women and their newborns underwent an examination of HBV immunological markers and HBV-DNA at regular intervals.
Results: 1 The positive rate of HBsAg of newborns (age=24h) in Group A was significantly lower than that in Group B.
2 The newborn's birth weigh, height, one-minute Apgar scores, neonatal jaundice, congenital malformation, sex and other combinations had no significant difference among Group I , Group II and Group III.
3 The incidence of postpartum hemorrhage, incisional infection, intrauterine infection had no significant difference among three groups.
4 The HBsAg positive rate in colostrums of Group A and that of Group B had no significant difference. The HBsAg positive rate in colostrums of subjects in Group A and B correlated positively to the HBeAg positive rate of materal blood, respectively.
5 As the infants were 6 months old, the positive rate of HBsAb was similar between Group I and Group II, The HBsAb positive rate of infants was signicantly higher in Group I than in Group III, there was not significant difference between Group II and Group III.
6 As the infants were 6 months old, the HBeAb positive rate infant blood had no significant difference between breast-feeding and artificial-feeding.
Conclusions: The pregnant women earring HBsAg should be given HBIG monthly during late pregnancy, offsprings should abtained HBIG and recombiant HBVac, these procedures can effectively reduce the positive rate of HBsAg of newborns.
引文
[1] Kane MA, Clements J, Hu D. Hepatitis B. Disease control priorities in developing countries. New York: Oxford University Press. 1993: 321-330.
[2] Mast EE, Alter MJ, Margolis HS. Strategies to prevent and control hepatitis B and C virus infections: A global perspective. Vaccine. 1999,17(13): 1730-1733.
[3] 钱宇平．流行病学．北京：人民卫生出版社．1998：38．
[4] Stevens CE, Neurath RA, Beasley RP, Szmuness W. HBeAg and anti-HBe detection by radioimmunoassay: correlation with vertical transmission of hepatitis B virus in Taiwan. J Med Virol. 1979, 3(3): 237-241.
[5] Beasley RP, Hwang LY, Lin CC, Stevens CE, Wang KY, Sun TS, Hsieh FJ, Szmuness W. Hepatitis B immune globulin (HBIG) efficacy in the interruption of perinatal transmission of hepatitis B virus carrier state. Initial report of a randomised double-blind placebo-controlled trial. Lancet. 1981, 2(8243): 388-393.
[6] Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SH, Chen RJ, Margolis HS, Huang CH, Maynard JE. Prevention of perinatal acquisition of hepatitis B virus carriage using vaccine: preliminary report of a randomized, double-blind placebo-controlled and comparative trial. Pediatrics. 1985, 76(5):713-718.
[7] Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol. 1977, 105(2):94-98.
[8] Beasley RP, Hwang LY, Lee GC, Lan CC, Roan CH, Huang FY, Chen CL. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B virus infections with hepatitis B immune globulin
and hepatitis B vaccine. Lancet. 1983, 2(8359): 1099-1102.
[9] 刘志华．乙型肝炎病毒宫内感染机制及预防措施的研究．国外医学妇幼保健分册．1999，10(1)：33-35．
[10] Lin HH, Lee TY, Chen DS, Sung JL, Ohto H, Etoh T, Kawana T, Minuno M. Transplacenal leakage of HBeAg-positive maternal blood as the most likely route in causing intrauterine infection with hepatitis B virus. Pediatrics. 1987, 111(6): 877-881.
[11] Ohto H, Lin HH, Kawana T, Etoh T, Tohyama H. Intrauterine transmission of hepatitis B virus is closely related to placental leakage. Medical virology. 1987, 21(1): 1-6.
[12] 刘志华，门可，徐德忠，闫永平，张景霞，徐剑秋，蒋美玲．乙型肝炎病毒宫内感染相关因素随访研究．中华预防医学杂志．1997，31(5)：263-265．
[13] 闫永平，徐德忠，王文亮，刘斌，刘志华，门可，徐剑秋．乙型肝炎表面抗原阳性孕妇不同孕期胎盘乙型肝炎病毒的感染状态．中华医学杂志．1998，78(1)：76-77．
[14] 徐德忠，闫永平，王素萍，刘蓬勃，白钢钻，王歆，史梦远，王雪萍．胎盘组织在乙型肝炎病毒宫内传播中的作用及其机制研究．中华医学杂志．2001，81(3)：176-177．
[15] Leung NW, Tam JS, Lau GT, Leung TW, Lau WY, Li AK. Hepatitis B virus DNA in peripheral blood leukocytes. A comparison between hepatocellular carcinoma and other hepatitis B virus-related chronic liver diseases. Cancer. 1994, 73(4): 1143-1148.
[16] Schimizu H, Mitsuda T, Fujita S, Yokota S. perinatal hepatitis B virus infection caused by antihepatitis Be positive maternal mononuclear cells. Arch Dis Child. 1991, 66(6): 718-721.
[17] Hadchouel M, Scotto J, Huret JL, Molinie C, Villa E, Deggos F, Brechot C. Presence of HBV DNA in spermatozoa: a possible vertical transmission of HBV via the germ line. J Med viral. 1985, 16(1): 61-66.
[18]周思亮，赵连三，黎飞．乙型肝炎患者卵细胞中检出乙肝病毒 DNA．遗传与疾病．1989，6：46．
[19]周思亮，赵连三，王锦蓉，刘丽，黎飞，彭海荣，曹钟梁，孟宪钦，陈渊卿，蒋惠秋，顾健人．乙肝病毒DNA在重症肝炎患者各器官组织中的分布及其意义．中华医学杂志．1988，68(8)：456-459．
[20]徐小元，刘逢举，田庚善．慢性HBV感染者精子中HBV-DNA存在的初步报告．兰州医学院学报．1987，14(1)：1-4．
[21]赵连三，刘晓松，张智翔，王锦蓉，刘丽，雷秉钧．乙型肝炎病毒感染经精子传播的可能性研究．中华传染病杂志．1998，16(3)：154-157．
[22]Lin HH, Kao JH, Hsu HY. Least microtransfusion from mother to fetus in elective cesarean delivery. Obstet Gynecol. 1996, 87(2): 244-248.
[23]Wong VC, Lee AK, Ip HM. Transmission of hepatitis B antigens from symptom free carrier mothers to the fetus and infant. Br J Obstet Gynecol. 1980, 87(11): 958-965.
[24]王清图，修霞，郭永，陶华娟．不同方案阻断乙肝病毒母婴垂直传播的临床研究．临床肝胆病杂志．2002，18(1)：51-52．
[25]刘颖琳，邝健全，张睿，黎淑芬，丁红，刘新质．胎儿感染乙型肝炎病毒的临床研究．中华妇产科杂志．2002，37(8)：465-468．
[26]王建设，朱启镕，张秀珍．分娩方式对乙型肝炎病毒母婴传播阻断效果的影响．中国医学杂志，2002，115(10)：1510-1512．
[27]王梦玖，生殖免疫学．第一版，中国展望出版社．1986：115-120．
[28]王小清，刘亦琪，孙亦骏，蒋涛．套式聚合酶链反应检测人乳中乙型肝炎病毒DNA．中华妇产科杂志．1996，31(1)：36-37．
[29]杨晓，崔敏娴，刘保根，邵蕊仪，刘如星，李冰如．乙型肝炎血清学指标阳性母亲哺乳问题的研究．中华妇产科杂志．1994，29(10)：586-588．
[30]Goh KT. Dengue a reemerging infectious disease in Singapore. Ann Acad Med Singapore. 1997, 26(5): 664-670.
[31]Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman PJ, Zhuang YL, Xu HF, Qian SG, Zhu QR. Long-term efficacy of active postexposure
immunization of infants for prevention of hepatitis B virus infection. United States-People's Republic of China Study Group on Hepatitis B. J Infect Dis. 1995: 171(1): 54-60.
[32] Ursi D, Leven M, Van Bever H, Quint W G, Niesters HG, Goossens H. Absence of hepatitis B virus (HBV) DNA in children born after exposure of their mothers to HBV during in vitro fertilization. J Clin Microbiol. 1994, 32(4): 3873-3875.
[33]闫永平，李瑞，徐德忠，陈长生，王雪萍．不同孕期乙型肝炎病毒宫内感染率差别的荟萃分析．第四军医大学学报．2002，23(9)：853-855．
[34]李小毛，施敏凤，杨越波，侯红英，沈慧敏．孕妇注射乙肝免疫球蛋白阻断HBV宫内传播的研究．中国优生与遗传杂志．2002，10(1)：63-67．
[35]朱启镕，于广军，吕晴，俞蕙，顾新焕，张秀珍，董左权．阻断乙型肝炎病毒宫内传播的随机对照研究．中华儿科杂志．2002，40(8)：478-480．
[36]岳亚飞，杨晓菊，张树林，韩晓兵．乙肝表面抗原阳性孕妇肌注乙肝免疫球蛋白预防母婴传播的临床研究．中国实用妇科与产科杂志．1999，15(9)：547-54．
[37] Ayoola EA, Johson AO. Hepatitis B vaccine in pregnancy: immunogenicity, safety and transfer of antibodies to infants. Int J Gynaecol Obstet. 1987, 25(4): 297-301.
[38]胡桂英，谭文华，马金赏，张景权，康志海．妊娠后期接种乙肝疫苗免疫效果的观察．实用妇产科杂志．1995，11(6)：310-311．
[39]岳亚飞，李银姬，张树林．孕妇主动与被动联合免疫预防乙型肝炎病毒宫内感染的临床研究．中国围产医学杂志．2000，3(1)：3-5．
[40]姚光弼．抗乙型肝炎病毒新药拉米夫定．中国新药与临床杂志．1998，17(6)：381-384．
[41] Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M.A Preliminary trial of Lamivudine for chronic hepatitis B infection. N Engl J Med. 1995, 333(25): 1657-1661.
[42] Lai CL, Ching CK, Jun AKM, Li E, Young J, Hill A, Wong BC, Dent J,
Wu PC. gamivudine is effective in suppressing hepatitis B virus DNA in Chinese hepatitis B surface antigen carriers: A placebo-controlled trial. Hepatology. 1997, 25(1): 241-244.
[43] Moodley J, Moodley D, Pillay K, Coovadia H, Saba J, Van Leeuwen R, Goodwin C, Harrigan PR, Moore KH, Stone C, Plumb R, John MA. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis.1998, 178 (5): 1327-1333.
[44] Van NUNEN AB, De Man RA, Heijtink RA, Niesters HG, Schalm SW. Lamivudine in the last 4 weeks of pregnancy to prevent perinatal transmission in highly viremic chronic hepatitis B patients. Journal of Hepatology. 2000, 32(6): 1040-1041.
[45] 高寿征主编．病毒肝炎防治研究．北京：北京出版社．1993：374．
[46] Sumazaki R, Motz M, Wolf H, Heinig J, Jilg W, Deinhardt F. Detection of hepatitis B virus in serum using amplification of viral DNA by means of polymerase chain reaction. J Med Virol. 1989, 27(4): 304-308.
[47] Burk RD, Hwang LY, Ho GY, Shafrita DA, Beasley RP. Outcome of perinatal hepatitis B virus exposure is dependent on matenal virus load. J Infect Dis. 1994, 170(6): 1418-1423.
[48] Akhter S, Talukder MQ, Bhuiyan Chowdhury TA, Islam MN, Begum S. Hepatitis B virus infection in pregnant mothers and its transmission to infants. Indian J Pediatr. 1992, 59(4): 411-415.
[49] Goudeau A. Lack of anti-HBc IgM in neonates with HBsAg carrier mothers argues against transplancental transmission of hepatitis B virus infection. Lancet. 1983, 2(8359): 1103-1104.
[50] Milich DR. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci. 1990, 87(17): 6599-6603.
[51] Gonzalez ML, Gonzalez JB, Salva F, Lardinois R. A 7-year follow-up of newborns vaccinated against hepatitis B. Vaccine. 1993, 11(10): 1033-1036.
[52] Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, Thomas HC. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet. 1989,2(8663): 588-591.
[53] Scott JS, Pan PE, Pace RA, Sloots TP, Cooksley WG. The absence of hepatitis B virus DNA in hepatitis B e antigen positive sera from chronic hepatitis B surface antigen carriers in china. J Med virol. 1990, 30(2): 103-106.
[54]彭文伟．传染病学．第四版．北京：人民卫生出版社．1995：16．
[55] Chang MH, Hsu HY, Huang LM, Lee PI, Lin HH, Lee CY. The Role of transplacental hepatitis B core antibody in the mother-to-infant transmission of hepatitisBvirus. Journal of Hepatology. 1996, 24(6):674-679.
[56] Iwarson S, Tabor E, Thomas HC, Snoy P, Gerety RJ. Protection against hepatitis B virus infection by immunization with hepatitis B core antigen. Gastroenterology. 1985, 88(3): 763-767.
[57] Chen WH, Yin CS, Chang YK, Yan JS, Chu ML. Neonatal Gastric aspirates as a predictor of perinatal hepatitis B virus infections. International Journal of Gynecology and Obstetrics. 1998, 60(1):15-21.
[58]易广才．乙型及丙型肝炎病毒的母婴传播．中国中国优生与遗传杂志．2000，8(5)：63-64．
[59]唐时幸，于光烈，程绍尧．HBV宫内感染及其频率的研究．中华流行病学杂志．1990，11(6)：328．
[60]Beasley RP. 乙肝病毒感染的母婴垂直传播．国外医学．流行病学与传染病学分册．1984，11(6)：258．
[61] Zhang SL, Han XB, Yue YF. Relationship between HBV viremia level of pregnant women and intrauterine infection: neated PCR for detection of HBVDNA. World J Gastroenterol. 1998, 4(1): 61-63.
[62]刘颖，庄依亮，产前注射乙型肝炎免疫球蛋白阻断乙型肝炎病毒宫内感染．中国新药与临床杂志．1999，18(2)：92-93．
[63]刘海英，马玉燕，崔保霞，戴(日文)笙，杨洁．孕妇乙肝免疫球蛋白被动免疫阻断 HBV 母婴垂直传播作用机理的研究．现代妇产科进展．2002，11(2)：128-130．
[64]赵淑华，韩丽英，张立会，孙玉秀．乙型肝炎病毒携带者妊娠对母婴的危害及预防措施的研究．白求恩医科大学学报．2000，26(1)：75-76．
[65]池肇春．新编实用肝病学．北京：中国医药科技出版社．1994，65-69．
[66] Borhanmanesh F, Beck G, Charles D. Pregnancy in patient with cirrhosis of the live. Obstet Gynecol. 1987, 36: 315-320.
[67]岳亚飞，张树林，门伯媛，吴玲，陈太平，王文莺，张蕴琪，李义方．乙肝病毒致畸作用的前瞻性研究．实用妇产科杂志．1996，12(4)：205-206．
[68]李国梁．30年(1957-1987)围产畸形儿的回顾分析和优生措施的探讨．新医学．1989，20(1)：19．
[69]花肇猛，曲际云，温焕新．新生儿先天畸形与孕妇乙型肝炎病毒感染关系的研究．中华流行病学杂志．1988，8(6)：360．
[70] Van OS HC, Drogendijk AC, Fetter WP, Heijtink RA, Zeilmaker GH. The influence of contamination of culture medium with hepatitis B virus on the outcom of in vitro fertilization pregnancies. Am J Obstet Gynecol. 1991, 165(1): 152-159.
[71] Kim SC, Chung EK. Immunogenicity of hepatitis B vaccine in preterm infants. Pediatrics. 1997, 99(4): 534-536.
[72]程蔚蔚，王采玉，张振钧，任世玲，徐志一．乙肝病毒血症与围产儿的关系．中国实用妇科与产科杂志．1993，9(5)：279-280．
[73]张志诚．临床产科学．天津：天津科学技术出版社．1994．
[74] Bertoletti A, Maini MK. Protection or damage: a dual role for the
virus-specific cytotoxin T lymphocyte response in hepatitis B and C infection? Curr Opin Microbiol. 2000, 3(4): 387-392.
[75] Huang K, Lin S. Nationwide vaccination: a success story in Taiwan. Vaccine. 2000, 18(suppll): 35-38.
[76] Wen YM, Wu XH, Hu DC, Zhang QP, Ouo SQ. Hepatitis B vaccine and anti-HBs complex as approach for vaccine therapy. Lancet. 1995, 345(8964):1575-1576.
[77]吕晴，段恕诚，朱启镕．乙型肝炎病毒疫苗联合应用乙肝高效价免疫球蛋白对乙肝免疫效果的观察．上海医科大学学报．1992，19(6)：448-451．
[78]金春子，沈平虎，李萍，邵明明，贾卉，王绮云．孕产妇和新生儿血清及初乳中检测HBV-DNA．中国优生与遗传杂志．2001，9(5)：61-62．
[79]张兰英，李晓平，付金凤，陈晓卿．乙肝病毒不同携带状态产妇的新生儿乙肝病毒感染危险性分析．新生儿科杂志．2000，15(5)：193-239．
[2] Mast EE, Alter MJ, Margolis HS. Strategies to prevent and control hepatitis B and C virus infections: A global perspective. Vaccine. 1999,17(13): 1730-1733.
[3] 钱宇平．流行病学．北京：人民卫生出版社．1998：38．
[4] Stevens CE, Neurath RA, Beasley RP, Szmuness W. HBeAg and anti-HBe detection by radioimmunoassay: correlation with vertical transmission of hepatitis B virus in Taiwan. J Med Virol. 1979, 3(3): 237-241.
[5] Beasley RP, Hwang LY, Lin CC, Stevens CE, Wang KY, Sun TS, Hsieh FJ, Szmuness W. Hepatitis B immune globulin (HBIG) efficacy in the interruption of perinatal transmission of hepatitis B virus carrier state. Initial report of a randomised double-blind placebo-controlled trial. Lancet. 1981, 2(8243): 388-393.
[6] Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SH, Chen RJ, Margolis HS, Huang CH, Maynard JE. Prevention of perinatal acquisition of hepatitis B virus carriage using vaccine: preliminary report of a randomized, double-blind placebo-controlled and comparative trial. Pediatrics. 1985, 76(5):713-718.
[7] Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol. 1977, 105(2):94-98.
[8] Beasley RP, Hwang LY, Lee GC, Lan CC, Roan CH, Huang FY, Chen CL. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B virus infections with hepatitis B immune globulin
and hepatitis B vaccine. Lancet. 1983, 2(8359): 1099-1102.
[9] 刘志华．乙型肝炎病毒宫内感染机制及预防措施的研究．国外医学妇幼保健分册．1999，10(1)：33-35．
[10] Lin HH, Lee TY, Chen DS, Sung JL, Ohto H, Etoh T, Kawana T, Minuno M. Transplacenal leakage of HBeAg-positive maternal blood as the most likely route in causing intrauterine infection with hepatitis B virus. Pediatrics. 1987, 111(6): 877-881.
[11] Ohto H, Lin HH, Kawana T, Etoh T, Tohyama H. Intrauterine transmission of hepatitis B virus is closely related to placental leakage. Medical virology. 1987, 21(1): 1-6.
[12] 刘志华，门可，徐德忠，闫永平，张景霞，徐剑秋，蒋美玲．乙型肝炎病毒宫内感染相关因素随访研究．中华预防医学杂志．1997，31(5)：263-265．
[13] 闫永平，徐德忠，王文亮，刘斌，刘志华，门可，徐剑秋．乙型肝炎表面抗原阳性孕妇不同孕期胎盘乙型肝炎病毒的感染状态．中华医学杂志．1998，78(1)：76-77．
[14] 徐德忠，闫永平，王素萍，刘蓬勃，白钢钻，王歆，史梦远，王雪萍．胎盘组织在乙型肝炎病毒宫内传播中的作用及其机制研究．中华医学杂志．2001，81(3)：176-177．
[15] Leung NW, Tam JS, Lau GT, Leung TW, Lau WY, Li AK. Hepatitis B virus DNA in peripheral blood leukocytes. A comparison between hepatocellular carcinoma and other hepatitis B virus-related chronic liver diseases. Cancer. 1994, 73(4): 1143-1148.
[16] Schimizu H, Mitsuda T, Fujita S, Yokota S. perinatal hepatitis B virus infection caused by antihepatitis Be positive maternal mononuclear cells. Arch Dis Child. 1991, 66(6): 718-721.
[17] Hadchouel M, Scotto J, Huret JL, Molinie C, Villa E, Deggos F, Brechot C. Presence of HBV DNA in spermatozoa: a possible vertical transmission of HBV via the germ line. J Med viral. 1985, 16(1): 61-66.
[18]周思亮，赵连三，黎飞．乙型肝炎患者卵细胞中检出乙肝病毒 DNA．遗传与疾病．1989，6：46．
[19]周思亮，赵连三，王锦蓉，刘丽，黎飞，彭海荣，曹钟梁，孟宪钦，陈渊卿，蒋惠秋，顾健人．乙肝病毒DNA在重症肝炎患者各器官组织中的分布及其意义．中华医学杂志．1988，68(8)：456-459．
[20]徐小元，刘逢举，田庚善．慢性HBV感染者精子中HBV-DNA存在的初步报告．兰州医学院学报．1987，14(1)：1-4．
[21]赵连三，刘晓松，张智翔，王锦蓉，刘丽，雷秉钧．乙型肝炎病毒感染经精子传播的可能性研究．中华传染病杂志．1998，16(3)：154-157．
[22]Lin HH, Kao JH, Hsu HY. Least microtransfusion from mother to fetus in elective cesarean delivery. Obstet Gynecol. 1996, 87(2): 244-248.
[23]Wong VC, Lee AK, Ip HM. Transmission of hepatitis B antigens from symptom free carrier mothers to the fetus and infant. Br J Obstet Gynecol. 1980, 87(11): 958-965.
[24]王清图，修霞，郭永，陶华娟．不同方案阻断乙肝病毒母婴垂直传播的临床研究．临床肝胆病杂志．2002，18(1)：51-52．
[25]刘颖琳，邝健全，张睿，黎淑芬，丁红，刘新质．胎儿感染乙型肝炎病毒的临床研究．中华妇产科杂志．2002，37(8)：465-468．
[26]王建设，朱启镕，张秀珍．分娩方式对乙型肝炎病毒母婴传播阻断效果的影响．中国医学杂志，2002，115(10)：1510-1512．
[27]王梦玖，生殖免疫学．第一版，中国展望出版社．1986：115-120．
[28]王小清，刘亦琪，孙亦骏，蒋涛．套式聚合酶链反应检测人乳中乙型肝炎病毒DNA．中华妇产科杂志．1996，31(1)：36-37．
[29]杨晓，崔敏娴，刘保根，邵蕊仪，刘如星，李冰如．乙型肝炎血清学指标阳性母亲哺乳问题的研究．中华妇产科杂志．1994，29(10)：586-588．
[30]Goh KT. Dengue a reemerging infectious disease in Singapore. Ann Acad Med Singapore. 1997, 26(5): 664-670.
[31]Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman PJ, Zhuang YL, Xu HF, Qian SG, Zhu QR. Long-term efficacy of active postexposure
immunization of infants for prevention of hepatitis B virus infection. United States-People's Republic of China Study Group on Hepatitis B. J Infect Dis. 1995: 171(1): 54-60.
[32] Ursi D, Leven M, Van Bever H, Quint W G, Niesters HG, Goossens H. Absence of hepatitis B virus (HBV) DNA in children born after exposure of their mothers to HBV during in vitro fertilization. J Clin Microbiol. 1994, 32(4): 3873-3875.
[33]闫永平，李瑞，徐德忠，陈长生，王雪萍．不同孕期乙型肝炎病毒宫内感染率差别的荟萃分析．第四军医大学学报．2002，23(9)：853-855．
[34]李小毛，施敏凤，杨越波，侯红英，沈慧敏．孕妇注射乙肝免疫球蛋白阻断HBV宫内传播的研究．中国优生与遗传杂志．2002，10(1)：63-67．
[35]朱启镕，于广军，吕晴，俞蕙，顾新焕，张秀珍，董左权．阻断乙型肝炎病毒宫内传播的随机对照研究．中华儿科杂志．2002，40(8)：478-480．
[36]岳亚飞，杨晓菊，张树林，韩晓兵．乙肝表面抗原阳性孕妇肌注乙肝免疫球蛋白预防母婴传播的临床研究．中国实用妇科与产科杂志．1999，15(9)：547-54．
[37] Ayoola EA, Johson AO. Hepatitis B vaccine in pregnancy: immunogenicity, safety and transfer of antibodies to infants. Int J Gynaecol Obstet. 1987, 25(4): 297-301.
[38]胡桂英，谭文华，马金赏，张景权，康志海．妊娠后期接种乙肝疫苗免疫效果的观察．实用妇产科杂志．1995，11(6)：310-311．
[39]岳亚飞，李银姬，张树林．孕妇主动与被动联合免疫预防乙型肝炎病毒宫内感染的临床研究．中国围产医学杂志．2000，3(1)：3-5．
[40]姚光弼．抗乙型肝炎病毒新药拉米夫定．中国新药与临床杂志．1998，17(6)：381-384．
[41] Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M.A Preliminary trial of Lamivudine for chronic hepatitis B infection. N Engl J Med. 1995, 333(25): 1657-1661.
[42] Lai CL, Ching CK, Jun AKM, Li E, Young J, Hill A, Wong BC, Dent J,
Wu PC. gamivudine is effective in suppressing hepatitis B virus DNA in Chinese hepatitis B surface antigen carriers: A placebo-controlled trial. Hepatology. 1997, 25(1): 241-244.
[43] Moodley J, Moodley D, Pillay K, Coovadia H, Saba J, Van Leeuwen R, Goodwin C, Harrigan PR, Moore KH, Stone C, Plumb R, John MA. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis.1998, 178 (5): 1327-1333.
[44] Van NUNEN AB, De Man RA, Heijtink RA, Niesters HG, Schalm SW. Lamivudine in the last 4 weeks of pregnancy to prevent perinatal transmission in highly viremic chronic hepatitis B patients. Journal of Hepatology. 2000, 32(6): 1040-1041.
[45] 高寿征主编．病毒肝炎防治研究．北京：北京出版社．1993：374．
[46] Sumazaki R, Motz M, Wolf H, Heinig J, Jilg W, Deinhardt F. Detection of hepatitis B virus in serum using amplification of viral DNA by means of polymerase chain reaction. J Med Virol. 1989, 27(4): 304-308.
[47] Burk RD, Hwang LY, Ho GY, Shafrita DA, Beasley RP. Outcome of perinatal hepatitis B virus exposure is dependent on matenal virus load. J Infect Dis. 1994, 170(6): 1418-1423.
[48] Akhter S, Talukder MQ, Bhuiyan Chowdhury TA, Islam MN, Begum S. Hepatitis B virus infection in pregnant mothers and its transmission to infants. Indian J Pediatr. 1992, 59(4): 411-415.
[49] Goudeau A. Lack of anti-HBc IgM in neonates with HBsAg carrier mothers argues against transplancental transmission of hepatitis B virus infection. Lancet. 1983, 2(8359): 1103-1104.
[50] Milich DR. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci. 1990, 87(17): 6599-6603.
[51] Gonzalez ML, Gonzalez JB, Salva F, Lardinois R. A 7-year follow-up of newborns vaccinated against hepatitis B. Vaccine. 1993, 11(10): 1033-1036.
[52] Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, Thomas HC. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet. 1989,2(8663): 588-591.
[53] Scott JS, Pan PE, Pace RA, Sloots TP, Cooksley WG. The absence of hepatitis B virus DNA in hepatitis B e antigen positive sera from chronic hepatitis B surface antigen carriers in china. J Med virol. 1990, 30(2): 103-106.
[54]彭文伟．传染病学．第四版．北京：人民卫生出版社．1995：16．
[55] Chang MH, Hsu HY, Huang LM, Lee PI, Lin HH, Lee CY. The Role of transplacental hepatitis B core antibody in the mother-to-infant transmission of hepatitisBvirus. Journal of Hepatology. 1996, 24(6):674-679.
[56] Iwarson S, Tabor E, Thomas HC, Snoy P, Gerety RJ. Protection against hepatitis B virus infection by immunization with hepatitis B core antigen. Gastroenterology. 1985, 88(3): 763-767.
[57] Chen WH, Yin CS, Chang YK, Yan JS, Chu ML. Neonatal Gastric aspirates as a predictor of perinatal hepatitis B virus infections. International Journal of Gynecology and Obstetrics. 1998, 60(1):15-21.
[58]易广才．乙型及丙型肝炎病毒的母婴传播．中国中国优生与遗传杂志．2000，8(5)：63-64．
[59]唐时幸，于光烈，程绍尧．HBV宫内感染及其频率的研究．中华流行病学杂志．1990，11(6)：328．
[60]Beasley RP. 乙肝病毒感染的母婴垂直传播．国外医学．流行病学与传染病学分册．1984，11(6)：258．
[61] Zhang SL, Han XB, Yue YF. Relationship between HBV viremia level of pregnant women and intrauterine infection: neated PCR for detection of HBVDNA. World J Gastroenterol. 1998, 4(1): 61-63.
[62]刘颖，庄依亮，产前注射乙型肝炎免疫球蛋白阻断乙型肝炎病毒宫内感染．中国新药与临床杂志．1999，18(2)：92-93．
[63]刘海英，马玉燕，崔保霞，戴(日文)笙，杨洁．孕妇乙肝免疫球蛋白被动免疫阻断 HBV 母婴垂直传播作用机理的研究．现代妇产科进展．2002，11(2)：128-130．
[64]赵淑华，韩丽英，张立会，孙玉秀．乙型肝炎病毒携带者妊娠对母婴的危害及预防措施的研究．白求恩医科大学学报．2000，26(1)：75-76．
[65]池肇春．新编实用肝病学．北京：中国医药科技出版社．1994，65-69．
[66] Borhanmanesh F, Beck G, Charles D. Pregnancy in patient with cirrhosis of the live. Obstet Gynecol. 1987, 36: 315-320.
[67]岳亚飞，张树林，门伯媛，吴玲，陈太平，王文莺，张蕴琪，李义方．乙肝病毒致畸作用的前瞻性研究．实用妇产科杂志．1996，12(4)：205-206．
[68]李国梁．30年(1957-1987)围产畸形儿的回顾分析和优生措施的探讨．新医学．1989，20(1)：19．
[69]花肇猛，曲际云，温焕新．新生儿先天畸形与孕妇乙型肝炎病毒感染关系的研究．中华流行病学杂志．1988，8(6)：360．
[70] Van OS HC, Drogendijk AC, Fetter WP, Heijtink RA, Zeilmaker GH. The influence of contamination of culture medium with hepatitis B virus on the outcom of in vitro fertilization pregnancies. Am J Obstet Gynecol. 1991, 165(1): 152-159.
[71] Kim SC, Chung EK. Immunogenicity of hepatitis B vaccine in preterm infants. Pediatrics. 1997, 99(4): 534-536.
[72]程蔚蔚，王采玉，张振钧，任世玲，徐志一．乙肝病毒血症与围产儿的关系．中国实用妇科与产科杂志．1993，9(5)：279-280．
[73]张志诚．临床产科学．天津：天津科学技术出版社．1994．
[74] Bertoletti A, Maini MK. Protection or damage: a dual role for the
virus-specific cytotoxin T lymphocyte response in hepatitis B and C infection? Curr Opin Microbiol. 2000, 3(4): 387-392.
[75] Huang K, Lin S. Nationwide vaccination: a success story in Taiwan. Vaccine. 2000, 18(suppll): 35-38.
[76] Wen YM, Wu XH, Hu DC, Zhang QP, Ouo SQ. Hepatitis B vaccine and anti-HBs complex as approach for vaccine therapy. Lancet. 1995, 345(8964):1575-1576.
[77]吕晴，段恕诚，朱启镕．乙型肝炎病毒疫苗联合应用乙肝高效价免疫球蛋白对乙肝免疫效果的观察．上海医科大学学报．1992，19(6)：448-451．
[78]金春子，沈平虎，李萍，邵明明，贾卉，王绮云．孕产妇和新生儿血清及初乳中检测HBV-DNA．中国优生与遗传杂志．2001，9(5)：61-62．
[79]张兰英，李晓平，付金凤，陈晓卿．乙肝病毒不同携带状态产妇的新生儿乙肝病毒感染危险性分析．新生儿科杂志．2000，15(5)：193-239．