乙型肝炎病毒宫内感染的随访研究
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摘要
目的 了解乙肝表面抗原(HBsAg)阳性孕妇及其孩子的转归情况，并以此评价既往判断新生儿发生HBV宫内感染指标的可靠性。同时，对HBsAg阳性孕妇孕期注射乙肝免疫球蛋白(HBIG)和新生儿联合使用HBIG与乙肝疫苗阻断HBV母婴传播的效果进行评价。
方法 对1993年3月至1997年3月，在陕西省妇幼保健院分娩的402例HBsAg阳性孕妇(孕期未用HBIG)及其孩子作为远期随访队列，进行随访以了解产妇及其孩子的转归情况。对2002年10月至2004年4月，在陕西省妇幼保健院分娩的108名HBsAg阳性孕妇(孕期用HBIG)及其新生儿作为近期随访队列，分别在婴儿1、3、6、12月龄，进行随访。同时以远期随访队列为对照，进行孕期HBIG干预效果的历史对照临床试验研究。在此基础上，对既往HBV宫内感染的诊断标准进行临床流行病学评价研究。所有血样HBV感染标志物采用酶联免疫吸附试验(ELISA)检测。谷丙转氨酶水平采用谷丙转氨酶试剂盒进行检测。数据统计学分析方法采用x~2检验、t检验、和Fisher精确概率法。
结果
1．随访结果：①远期随访队列402例HBsAg阳性孕妇所生婴儿中205例既往曾在婴儿出生1年内进行过近期随访，随访了其中的106例。在婴儿出生6年后对402例母亲及其孩子进行远期随访，随访到其中的59例。②近期随访队列108例HBsAg阳性孕妇所生婴儿111例(其中3例是双胞胎)，婴儿出生1年内的近期随访中，随访了其
第四军医大学硕士学位论文
中的85例婴儿。
2.母婴转归:
(l)远期随访队列:205例婴儿出生时n例HBsAg阳性。近期随访
中9例持续阳性，2例转阴。另外5例出生时HBsAg阴性在随访期
间HBsAg转阳。近期随访期间总HBsAg阳性率为13.2%(14/106)，
87.5%(14/16)转为慢性HBV感染。其中81例随访期间检测抗一HBS，
n例婴儿为阴性，免疫无应答率为13.6%(11/81)。远期随访到的
59例儿童出生时的HBV宫内感染率为8.5%(5/59)，60%(3/5)转
为慢性HBV感染。乙肝疫苗免疫无应答率为13.6%(8/59)。母亲分
娩前后的HBeAg转换明显，分娩后84.6%(11/13)转阴。
(2)近期随访队列:近期随访的85例婴儿中4例出生时HBsAg阳性，
婴儿1月龄时其中3例转阴，3月龄时，全部转阴，直到8月龄时
其中1例婴儿的HBsAg再次转阳。随访期间总HBsAg阳性率为1.2
%(1/85)，25%(1/4)形成慢性化。抗一HBS转阳率在婴儿1月
龄时为98.8%(84/85)，3月龄时为100%，直到8月龄时，HBsAg
再次转阳的婴儿抗一HBs转阴，到12月龄时仍为98.8%，免疫无应
答率为1.2%。新生儿出生时外周血15.3%可检测到HBeAg，随访时
50%可检测到抗一HBe和100%可检测到抗一HBc。婴儿1月龄时
HBeAgl 00%消退;抗一HBe在婴儿6月龄时开始消退，12月龄时100
%的婴儿消退;抗一HBc持续时间最长，婴儿7月龄时开始消退，12
月龄时仍有38%的婴儿未消退。
3.宫内感染率:
在孕期未用HBIG的情况下
(l)以新生儿出生时外周血HBV DNA阳性为诊断指标，HBV宫内感
染率为3.7%(巧/- 402);以新生儿血HBsAg为诊断指标，宫内感
染率为3.5%(14/402)。
(2)以近期随访为标准，将HBsAg转阳的婴儿包括在内，HBV宫内
感染率为6.8%(14/205)。
第四军医大学硕士学位论文
(3)以远期随访为标准，HBV宫内感染率为5.1%(3/59)。
在孕期用HBIG的情况下
(l)以新生儿出生时外周血HBsAg阳性为诊断标准，HBV宫内感染
率为5.5%(6/108)。
(2)以近期随访为标准，HBV宫内感染率为0.9%(1/108)。
4.HBIG的干预效果:近期随访队列为HBIG干预组，远期随访队列
为对照组，两组新生儿出生时的HBV宫内感染率无显著差异(P>
0.05，xZ=0.26)。近期随访中合并 HBsAg转阳的婴儿后，两组婴儿
的HBV宫内感染率差异显著(x’二5.40，P<0.05)。婴儿发生HBV
宫内感染后形成的慢性化两组差异显著(x’=5.59，P<0.05)。婴
儿的乙肝疫苗免疫无应答率两组差异显著(x’=9.52，P<0.05)。
结论
1.HBsAg阳性孕妇所生新生儿的HBV宫内感染率为3.7%一6.8%。
经随访，可避免漏检一部分发生宫内感染的婴儿，提高宫内感染的
检出率。
2.宫内感染HBV的婴儿转为慢性HBV感染，主要与孕妇HBeAg阳
性有关。婴儿的免疫无应答与宫内感染有关。新生儿HBV宫内感染
与其HBSAg阳性孕妇既往HBsAg、HBeAg阳性有关。HBsAg阳性孕妇
产后血清HBV标志物的显著变化提示，孕期可能处于免疫耐受阶段，
这种状况使胎儿发生宫内感染的机率增大。
3.HBsAg阳性孕妇孕期用HBIG和新生儿用HB工G和乙肝疫苗联合免
疫，可降低宫内感染、阻断婴儿的HBsAg阳转和宫内感染形成的慢
性化，提高疫苗的保护率。母血中的HBeAg、抗一HBe和抗一HBc可经
胎盘进入胎儿体内。
4.在孕期未用HBIG的情况下，近期随访的宫内感染率比出生时的
宫内感染率可能更准确。在孕期和新生儿注射HBIG干预措施的影
响下，以出生时新生)叻卜周血HBsAg阳性诊断HBV宫内感染较为合
适。因此，对HBsAg阳性母亲的新生儿检测外周血HBV DNA/HBsAg，
第四军医大学硕士学位论文
并做动态观察，可能会对HBV的宫内感染较为准确的判断。
AIM: To observe the sequel of hepatitis B virus (HBV) intrauterine infection by follow-up study. To further estimate the reliability of previous criteria to diagnose HBV intrauterine infection, and to evaluate the blocking effect on HBV mother to infant transmission through injecting HBsAg positive mothers during the third trimester of pregnancy with hepatitis B immunoglobulin (HBIG) and combined injecting infants with HBIG and HB vaccine.
METHODS: A group of 402 children of HBsAg positive mothers were recruited into our study from 1993 to 1997 in Maternal and Children Health Hospital of Shaanxi Province. The mothers were not injected with HBIG and were defined as the historical control group. They served as long-term follow-up cohort, and were followed up to observe the sequel of HBV infection. Another group of 108 infants of HBsAg-positive mothers were recruited into our study from 2002 to 2004 in the same Hospital. They served as short-term follow-up cohort. The mothers were injected with HBIG during the third trimester of
pregnancy and were defined as the HBIG group. The infants received HBIG immediately after birth and HB vaccine at 0, 1, 6 month of age. All of infants of HBIG group were followed up at 1, 3, 6 and 12 month of age to study the efficacy of HBIG for interruption of HBV mother-infant transmission. HBV markers including HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc in sera of all subjects were detected by enzyme-linked immunosorbent assay (ELISA). In the blood samples of followed-up children and their mothers, sera alanine transaminase (ALT) levels were assayed by autoanalyzer. The data were analyzed by t-test, x 2 test and Fisher probabilities with SPSS software. RESULTS:
(1) In long-term follow-up cohort, the intrauterine infection rate of HBV among 402 children was 3.7%. Among 402, 205 infants were followed up and 106 of them were followed up actually. Within 205 infants, 11 infants were positive for HBsAg at birth. Among the 11 infants, 9 infants were HBsAg positive persistently, 2 infants became negative for HBsAg. Another 5 infants became positive for HBsAg and lasted for 6.3 months on average. During short-term follow-up cohort, the intrauterine infection rate of HBV was 6. 8%( 14/205), the chronic infection rate of HBV was 87.5%(14/16). Of the infants followed up, anti-HBs in sera of 81 infants were tested, out of which, 11 infants were anti-HBs negative, and the rate of non-respondent to HB vaccine was
(2) Among the long-term follow-up cohort, 59 pairs of children and their mothers were followed up. The intrauterine infection rate of HBV was 8.5%( 5/59) at birth, and 5.1%(3/59) in long-term follow-up. The chronic infection rate of HBV was 60%(3/5). The non-respondent rate to HB vaccine was 13.6%(8/59). Obvious differences were found in
mothers' sera HBV markers before and after delivery. Among the 59 mothers, 13 mothers were HBeAg positive before delivery but 84.6%(11/13) mothers became HBeAg negative after delivery.
(3) Among the short-term follow-up cohort, 6 infants were HBsAg positive at birth, the intrauterine infection rate of HBV was 5.5%(6/108). Among the 108 infants, 85 were followed up at 1, 3, 6 and 12 month of age, respectively. Among the 85 infants, 4 were HBsAg positive at birth. One of the 4 infants became persistently positive for HBsAg, the rest 3 became negative during follow-up. The chronic infection rate of HBV was 25%(l/4) during follow-up. The responsive rate to HB vaccine was 98.8%(84/85). HBeAg, anti-HBe, anti-HBc in sera of neonates could be testable. At the first month of age, HBeAg entirely disappeared in sera of infants. Anti-HBe began to fade away at sixth month of age and entirely disappear at twelfth month of age. Anti-HBc lasted longer and began to fade away at seventh month of age, 38% of them were still positive at twelfth month of age.
(4) When mothers take no prevention measures during pregnancy, the intrauterine infection rate of HBV was 3.7% at birth, 6.8% during short-term follow up and 5.1% during long-term follow-
方法 对1993年3月至1997年3月，在陕西省妇幼保健院分娩的402例HBsAg阳性孕妇(孕期未用HBIG)及其孩子作为远期随访队列，进行随访以了解产妇及其孩子的转归情况。对2002年10月至2004年4月，在陕西省妇幼保健院分娩的108名HBsAg阳性孕妇(孕期用HBIG)及其新生儿作为近期随访队列，分别在婴儿1、3、6、12月龄，进行随访。同时以远期随访队列为对照，进行孕期HBIG干预效果的历史对照临床试验研究。在此基础上，对既往HBV宫内感染的诊断标准进行临床流行病学评价研究。所有血样HBV感染标志物采用酶联免疫吸附试验(ELISA)检测。谷丙转氨酶水平采用谷丙转氨酶试剂盒进行检测。数据统计学分析方法采用x~2检验、t检验、和Fisher精确概率法。
结果
1．随访结果：①远期随访队列402例HBsAg阳性孕妇所生婴儿中205例既往曾在婴儿出生1年内进行过近期随访，随访了其中的106例。在婴儿出生6年后对402例母亲及其孩子进行远期随访，随访到其中的59例。②近期随访队列108例HBsAg阳性孕妇所生婴儿111例(其中3例是双胞胎)，婴儿出生1年内的近期随访中，随访了其
第四军医大学硕士学位论文
中的85例婴儿。
2.母婴转归:
(l)远期随访队列:205例婴儿出生时n例HBsAg阳性。近期随访
中9例持续阳性，2例转阴。另外5例出生时HBsAg阴性在随访期
间HBsAg转阳。近期随访期间总HBsAg阳性率为13.2%(14/106)，
87.5%(14/16)转为慢性HBV感染。其中81例随访期间检测抗一HBS，
n例婴儿为阴性，免疫无应答率为13.6%(11/81)。远期随访到的
59例儿童出生时的HBV宫内感染率为8.5%(5/59)，60%(3/5)转
为慢性HBV感染。乙肝疫苗免疫无应答率为13.6%(8/59)。母亲分
娩前后的HBeAg转换明显，分娩后84.6%(11/13)转阴。
(2)近期随访队列:近期随访的85例婴儿中4例出生时HBsAg阳性，
婴儿1月龄时其中3例转阴，3月龄时，全部转阴，直到8月龄时
其中1例婴儿的HBsAg再次转阳。随访期间总HBsAg阳性率为1.2
%(1/85)，25%(1/4)形成慢性化。抗一HBS转阳率在婴儿1月
龄时为98.8%(84/85)，3月龄时为100%，直到8月龄时，HBsAg
再次转阳的婴儿抗一HBs转阴，到12月龄时仍为98.8%，免疫无应
答率为1.2%。新生儿出生时外周血15.3%可检测到HBeAg，随访时
50%可检测到抗一HBe和100%可检测到抗一HBc。婴儿1月龄时
HBeAgl 00%消退;抗一HBe在婴儿6月龄时开始消退，12月龄时100
%的婴儿消退;抗一HBc持续时间最长，婴儿7月龄时开始消退，12
月龄时仍有38%的婴儿未消退。
3.宫内感染率:
在孕期未用HBIG的情况下
(l)以新生儿出生时外周血HBV DNA阳性为诊断指标，HBV宫内感
染率为3.7%(巧/- 402);以新生儿血HBsAg为诊断指标，宫内感
染率为3.5%(14/402)。
(2)以近期随访为标准，将HBsAg转阳的婴儿包括在内，HBV宫内
感染率为6.8%(14/205)。
第四军医大学硕士学位论文
(3)以远期随访为标准，HBV宫内感染率为5.1%(3/59)。
在孕期用HBIG的情况下
(l)以新生儿出生时外周血HBsAg阳性为诊断标准，HBV宫内感染
率为5.5%(6/108)。
(2)以近期随访为标准，HBV宫内感染率为0.9%(1/108)。
4.HBIG的干预效果:近期随访队列为HBIG干预组，远期随访队列
为对照组，两组新生儿出生时的HBV宫内感染率无显著差异(P>
0.05，xZ=0.26)。近期随访中合并 HBsAg转阳的婴儿后，两组婴儿
的HBV宫内感染率差异显著(x’二5.40，P<0.05)。婴儿发生HBV
宫内感染后形成的慢性化两组差异显著(x’=5.59，P<0.05)。婴
儿的乙肝疫苗免疫无应答率两组差异显著(x’=9.52，P<0.05)。
结论
1.HBsAg阳性孕妇所生新生儿的HBV宫内感染率为3.7%一6.8%。
经随访，可避免漏检一部分发生宫内感染的婴儿，提高宫内感染的
检出率。
2.宫内感染HBV的婴儿转为慢性HBV感染，主要与孕妇HBeAg阳
性有关。婴儿的免疫无应答与宫内感染有关。新生儿HBV宫内感染
与其HBSAg阳性孕妇既往HBsAg、HBeAg阳性有关。HBsAg阳性孕妇
产后血清HBV标志物的显著变化提示，孕期可能处于免疫耐受阶段，
这种状况使胎儿发生宫内感染的机率增大。
3.HBsAg阳性孕妇孕期用HBIG和新生儿用HB工G和乙肝疫苗联合免
疫，可降低宫内感染、阻断婴儿的HBsAg阳转和宫内感染形成的慢
性化，提高疫苗的保护率。母血中的HBeAg、抗一HBe和抗一HBc可经
胎盘进入胎儿体内。
4.在孕期未用HBIG的情况下，近期随访的宫内感染率比出生时的
宫内感染率可能更准确。在孕期和新生儿注射HBIG干预措施的影
响下，以出生时新生)叻卜周血HBsAg阳性诊断HBV宫内感染较为合
适。因此，对HBsAg阳性母亲的新生儿检测外周血HBV DNA/HBsAg，
第四军医大学硕士学位论文
并做动态观察，可能会对HBV的宫内感染较为准确的判断。
AIM: To observe the sequel of hepatitis B virus (HBV) intrauterine infection by follow-up study. To further estimate the reliability of previous criteria to diagnose HBV intrauterine infection, and to evaluate the blocking effect on HBV mother to infant transmission through injecting HBsAg positive mothers during the third trimester of pregnancy with hepatitis B immunoglobulin (HBIG) and combined injecting infants with HBIG and HB vaccine.
METHODS: A group of 402 children of HBsAg positive mothers were recruited into our study from 1993 to 1997 in Maternal and Children Health Hospital of Shaanxi Province. The mothers were not injected with HBIG and were defined as the historical control group. They served as long-term follow-up cohort, and were followed up to observe the sequel of HBV infection. Another group of 108 infants of HBsAg-positive mothers were recruited into our study from 2002 to 2004 in the same Hospital. They served as short-term follow-up cohort. The mothers were injected with HBIG during the third trimester of
pregnancy and were defined as the HBIG group. The infants received HBIG immediately after birth and HB vaccine at 0, 1, 6 month of age. All of infants of HBIG group were followed up at 1, 3, 6 and 12 month of age to study the efficacy of HBIG for interruption of HBV mother-infant transmission. HBV markers including HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc in sera of all subjects were detected by enzyme-linked immunosorbent assay (ELISA). In the blood samples of followed-up children and their mothers, sera alanine transaminase (ALT) levels were assayed by autoanalyzer. The data were analyzed by t-test, x 2 test and Fisher probabilities with SPSS software. RESULTS:
(1) In long-term follow-up cohort, the intrauterine infection rate of HBV among 402 children was 3.7%. Among 402, 205 infants were followed up and 106 of them were followed up actually. Within 205 infants, 11 infants were positive for HBsAg at birth. Among the 11 infants, 9 infants were HBsAg positive persistently, 2 infants became negative for HBsAg. Another 5 infants became positive for HBsAg and lasted for 6.3 months on average. During short-term follow-up cohort, the intrauterine infection rate of HBV was 6. 8%( 14/205), the chronic infection rate of HBV was 87.5%(14/16). Of the infants followed up, anti-HBs in sera of 81 infants were tested, out of which, 11 infants were anti-HBs negative, and the rate of non-respondent to HB vaccine was
(2) Among the long-term follow-up cohort, 59 pairs of children and their mothers were followed up. The intrauterine infection rate of HBV was 8.5%( 5/59) at birth, and 5.1%(3/59) in long-term follow-up. The chronic infection rate of HBV was 60%(3/5). The non-respondent rate to HB vaccine was 13.6%(8/59). Obvious differences were found in
mothers' sera HBV markers before and after delivery. Among the 59 mothers, 13 mothers were HBeAg positive before delivery but 84.6%(11/13) mothers became HBeAg negative after delivery.
(3) Among the short-term follow-up cohort, 6 infants were HBsAg positive at birth, the intrauterine infection rate of HBV was 5.5%(6/108). Among the 108 infants, 85 were followed up at 1, 3, 6 and 12 month of age, respectively. Among the 85 infants, 4 were HBsAg positive at birth. One of the 4 infants became persistently positive for HBsAg, the rest 3 became negative during follow-up. The chronic infection rate of HBV was 25%(l/4) during follow-up. The responsive rate to HB vaccine was 98.8%(84/85). HBeAg, anti-HBe, anti-HBc in sera of neonates could be testable. At the first month of age, HBeAg entirely disappeared in sera of infants. Anti-HBe began to fade away at sixth month of age and entirely disappear at twelfth month of age. Anti-HBc lasted longer and began to fade away at seventh month of age, 38% of them were still positive at twelfth month of age.
(4) When mothers take no prevention measures during pregnancy, the intrauterine infection rate of HBV was 3.7% at birth, 6.8% during short-term follow up and 5.1% during long-term follow-
引文
[1] Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, 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.
[2] 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 post exposure 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.
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