夫妇双方乙肝病毒感染之亲子垂直传播的危险因素及基因型研究
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摘要
目的
探讨夫妇双方均为乙肝病毒（HBV）感染者，其亲子垂直传播的危险因素及基因型，为降低HBV亲子垂直传播提供科学依据。
方法
选择2010年8月—2011年11月在福建省妇幼保健院行产前初诊检查的孕妇，其HBsAg或HBV-DNA阳性、丈夫HBsAg或HBV-DNA阳性并决定住本院分娩的家庭；夫妇双方知情同意参与有关血或精液(丈夫) HBVM及HBV-DNA载量和基因型检测；分娩前再次抽血确定：孕妇血清HBsAg阳性，并收集新生儿脐带血。入选的研究家庭有58个，排除因故未收集到脐带血，符合入选条件的家庭有46个。采用酶联免疫吸附法（ELISA）检测HBVM，荧光定量PCR法（FQ-PCR）检测夫妇双方血清和精液HBV-DNA载量，型特异性引物和高分辨率溶解曲线测定乙肝病毒基因型。
结果
1.新生儿脐带血HBV-DNA阳性率为45.7%（21/46）。经单因素分析，孕妇血清HBsAg阳性HBVM不同模式、孕妇血清HBeAg阳性、孕妇血清HBV-DNA阳性及其血清HBV-DNA载量、父亲血清HBsAg阳性HBVM不同模式、父亲血清HBeAg阳性、父亲血清HBV-DNA阳性及其血清HBV-DNA载量有统计学意义(P＜0.05)；经多因素分析孕妇血清HBV-DNA阳性、父亲血清HBV-DNA载量仍有统计学意义(P＜0.05)，孕妇血清HBV-DNA阳性伴父亲血清HBV-DNA载量未见交互作用（P>0.05）。夫妇双方血清HBV-DNA载量均与新生儿脐带血HBV-DNA载量存在剂量反应关系,受试者工作特征曲线（ROC曲线）分析表明：孕妇血清HBV-DNA载量在1000copies/ml,父亲血清HBV-DNA载量在10000copies/ml是预测HBV垂直传播发生的最佳分界点，因为预测的敏感性与特异性较高。
2.孕妇血清HBV-DNA载量与脐带血HBV-DNA载量呈正相关，其血清HBV-DNA载量>脐带血HBV-DNA载量。
3.父亲血清HBV-DNA载量与脐带血HBV-DNA载量呈正相关,其血清HBV-DNA载量>脐带血HBV-DNA载量。
4.父亲血清HBV-DNA载量与精液HBV-DNA载量呈正相关，其血清HBV-DNA载量>精液HBV-DNA载量。
5．孕妇血清HBV-DNA阳性率为52.2%（24/46），父亲血清HBV-DNA阳性率为69.6%（32/46），精液HBV-DNA阳性率为22.6%（7/31），均与抽血孕周无相关。
6.脐带血HBVM检测HBsAg阳性率为34.8%（16/46）,HBeAg阳性率为23.9%（11/46）。
7.病例组与对照组在孕产史，夫妇双方乙肝携带时间、一级家族史、肝功能、乙肝相关保健知识知晓情况和新生儿结局等情况类似,均无统计学意义(P均＞0.05)。
8.夫妇双方为HBV感染者，将23个家庭69份血清标本进行基因检测，基因型以B型为主，还有少量C型。9个家庭夫妇及其新生儿均为B型；10个家庭以父婴传播为主，其中7个家庭父婴均为B型，3个家庭父婴为C型；4个家庭以母婴传播为主，母儿均为B型。
9. C型的父亲血清HBV-DNA载量高于B型。
10.脐带血HBV-DNA阳性新生儿随访至第7个月时，阴转率为15.0%（3/20）。
结论
1.孕妇血清HBV-DNA阳性、父亲血清HBV-DNA载量是HBV垂直传播的危险因素。
2.孕妇血清HBV-DNA载量与脐带血HBV-DNA载量呈正相关，其血清HBV-DNA载量>脐带血HBV-DNA载量；父亲血清HBV-DNA载量与脐带血HBV-DNA载量呈正相关，其血清HBV-DNA载量>脐带血HBV-DNA载量；父亲血清HBV-DNA载量与精液HBV-DNA载量呈正相关，其血清HBV-DNA载量>精液HBV-DNA载量。
3.孕妇血清HBV-DNA阳性伴父亲血清HBV-DNA载量不增加HBV垂直传播的危险。
4.从分子水平进一步证实HBV不仅能通过母亲传给后代，而且能通过父亲精子传给后代，基因型以B型为主，还有少量C型。
5. C型的父亲血清HBV-DNA载量高于B型。
Objective
To explore the risk factors and genotype of vertical transmission of HBVfrom HBsAg or HBV-DNA positive couple to infant,providing effective andscientific HBV prevention measures.
Methods
46families who had antenatal examination, pregnancy check-ups and gavebirth at Fujian Provincal Maternal and Child Health Hospital during August2010to November2011were chosen as research object. The information ofpregnant women，their husbands and their newborns were collected.Thosecouples’blood,hushands’sperm during pregnancy follow-up and justbefore delivery as well as their infants’ umbilical cord blood werecollected for related indicators detection.HBV serological markers wereanalysed by ELISA. HBV-DNA load and genotypes of HBV were analysed byfluorescent quantification-PCR (FQ-PCR) and type specific primers andhigh-resolution melting curve respectively.
Results
1.The positive rate of neonatal cord blood HBV-DNA was45.7%（21/46）.Univariate analysis showed that couple serum HBsAg-positiveHBVM different mode, couple serum HBeAg-positive, couple serum HBV-DNApositive，and couple serum HBV-DNA load were statistically significant(P<0.05). Using multivariate analysis to eliminate the effect ofconfounding factors, maternal serum HBV-DNA positive and paternal serumHBV-DNA load were still statistically significant(P<0.05).Maternal serumHBV-DNA positive and paternal serum HBV-DNA load did not show anyinteraction.There were dose-response relationship between couple serumHBV-DNA load level and neonatal cord blood HBV-DNA load level. The analysis of ROC curve showed that maternal serum HBV-DNA load level (1000copies/ml) and paternal serum HBV-DNA load level (10000copies/ml) werebetter demarcation point to forecast the occurrence of verticaltransmission of HBV from HBsAg or HBV-DNA positive couple toinfant,because there were better sensitivity and specificity duringforecast.
2.The maternal serum HBV-DNA load was positively correlated with thecord blood HBV-DNA load and the load level of maternal serum HBV-DNA washigher than cord blood HBV-DNA.
3.The paternal serum HBV-DNA load was positively correlated with thecord blood HBV-DNA load and the load level of paternal serum HBV-DNA washigher than cord blood HBV-DNA.
4.The paternal serum HBV-DNA load was positively correlated with semenHBV-DNA load and the load level of paternal serum HBV-DNA was higher thansemen HBV-DNA.
5. The positive rate of semen HBV-DNA was22.6%. while the positive rateof maternal serum HBV-DNA and paternal serum HBV-DNA were52.2%（24/46）and69.6%（32/46）respectively. All three were no relationships withgestational age.
6.The positive rate of cord blood HBsAg was34.8%（16/46） while thepositive rate of cord blood HBeAg was23.9%（11/46）.
7.The history of pregnancy,couple’s first class family history and HBVcarried time, liver function and neonatal outcome were no significantdifference between the case group and the control group (P>0.05).
8.23families total69portions serum samples were analysed genotype,the HBV genotype was dominant with B genotype, as well as a small amountof C genotype.9families were both couple and infant with B genotype.10families from paternal transmission included7families with Bgenotype,the else with C genotype.While4families from maternal transmission were B genotype.
9.Genotype C of paternal serum HBV-DNA load was higher than genotype B.
10. The negative conversion rate was15%(3/20) when HBV-DNA positiveinfants were followed up to7months.
Conclusion
1.Maternal serum HBV-DNA positive and paternal serum HBV-DNA load wererisk factors of vertical transmission of HBV from HBsAg or HBV-DNApositive couple to infant.
2. The couple serum HBV-DNA load was positively correlated with the cordblood HBV-DNA load and the load levels of couple serum HBV-DNA were higherthan cord blood HBV-DNA. The paternal serum HBV-DNA load was positivelycorrelated with semen HBV-DNA load and the load level of paternal serumHBV-DNA was higher than semen HBV-DNA.
3. Maternal serum HBV-DNA positive and paternal serum HBV-DNA load didnot increase the risk of vertical transmission of HBV from HBsAg or HBV-DNApositive couple to infant.
4.This study provided further evidence of vertical transmission of HBVnot only by maternal transmission,but also by paternal transmission atmolecular level. The genotype mostly were B genotype, as well as a smallamount of C genotype.
5.Genotype C of paternal serum HBV-DNA load was higher than genotype B.
探讨夫妇双方均为乙肝病毒（HBV）感染者，其亲子垂直传播的危险因素及基因型，为降低HBV亲子垂直传播提供科学依据。
方法
选择2010年8月—2011年11月在福建省妇幼保健院行产前初诊检查的孕妇，其HBsAg或HBV-DNA阳性、丈夫HBsAg或HBV-DNA阳性并决定住本院分娩的家庭；夫妇双方知情同意参与有关血或精液(丈夫) HBVM及HBV-DNA载量和基因型检测；分娩前再次抽血确定：孕妇血清HBsAg阳性，并收集新生儿脐带血。入选的研究家庭有58个，排除因故未收集到脐带血，符合入选条件的家庭有46个。采用酶联免疫吸附法（ELISA）检测HBVM，荧光定量PCR法（FQ-PCR）检测夫妇双方血清和精液HBV-DNA载量，型特异性引物和高分辨率溶解曲线测定乙肝病毒基因型。
结果
1.新生儿脐带血HBV-DNA阳性率为45.7%（21/46）。经单因素分析，孕妇血清HBsAg阳性HBVM不同模式、孕妇血清HBeAg阳性、孕妇血清HBV-DNA阳性及其血清HBV-DNA载量、父亲血清HBsAg阳性HBVM不同模式、父亲血清HBeAg阳性、父亲血清HBV-DNA阳性及其血清HBV-DNA载量有统计学意义(P＜0.05)；经多因素分析孕妇血清HBV-DNA阳性、父亲血清HBV-DNA载量仍有统计学意义(P＜0.05)，孕妇血清HBV-DNA阳性伴父亲血清HBV-DNA载量未见交互作用（P>0.05）。夫妇双方血清HBV-DNA载量均与新生儿脐带血HBV-DNA载量存在剂量反应关系,受试者工作特征曲线（ROC曲线）分析表明：孕妇血清HBV-DNA载量在1000copies/ml,父亲血清HBV-DNA载量在10000copies/ml是预测HBV垂直传播发生的最佳分界点，因为预测的敏感性与特异性较高。
2.孕妇血清HBV-DNA载量与脐带血HBV-DNA载量呈正相关，其血清HBV-DNA载量>脐带血HBV-DNA载量。
3.父亲血清HBV-DNA载量与脐带血HBV-DNA载量呈正相关,其血清HBV-DNA载量>脐带血HBV-DNA载量。
4.父亲血清HBV-DNA载量与精液HBV-DNA载量呈正相关，其血清HBV-DNA载量>精液HBV-DNA载量。
5．孕妇血清HBV-DNA阳性率为52.2%（24/46），父亲血清HBV-DNA阳性率为69.6%（32/46），精液HBV-DNA阳性率为22.6%（7/31），均与抽血孕周无相关。
6.脐带血HBVM检测HBsAg阳性率为34.8%（16/46）,HBeAg阳性率为23.9%（11/46）。
7.病例组与对照组在孕产史，夫妇双方乙肝携带时间、一级家族史、肝功能、乙肝相关保健知识知晓情况和新生儿结局等情况类似,均无统计学意义(P均＞0.05)。
8.夫妇双方为HBV感染者，将23个家庭69份血清标本进行基因检测，基因型以B型为主，还有少量C型。9个家庭夫妇及其新生儿均为B型；10个家庭以父婴传播为主，其中7个家庭父婴均为B型，3个家庭父婴为C型；4个家庭以母婴传播为主，母儿均为B型。
9. C型的父亲血清HBV-DNA载量高于B型。
10.脐带血HBV-DNA阳性新生儿随访至第7个月时，阴转率为15.0%（3/20）。
结论
1.孕妇血清HBV-DNA阳性、父亲血清HBV-DNA载量是HBV垂直传播的危险因素。
2.孕妇血清HBV-DNA载量与脐带血HBV-DNA载量呈正相关，其血清HBV-DNA载量>脐带血HBV-DNA载量；父亲血清HBV-DNA载量与脐带血HBV-DNA载量呈正相关，其血清HBV-DNA载量>脐带血HBV-DNA载量；父亲血清HBV-DNA载量与精液HBV-DNA载量呈正相关，其血清HBV-DNA载量>精液HBV-DNA载量。
3.孕妇血清HBV-DNA阳性伴父亲血清HBV-DNA载量不增加HBV垂直传播的危险。
4.从分子水平进一步证实HBV不仅能通过母亲传给后代，而且能通过父亲精子传给后代，基因型以B型为主，还有少量C型。
5. C型的父亲血清HBV-DNA载量高于B型。
Objective
To explore the risk factors and genotype of vertical transmission of HBVfrom HBsAg or HBV-DNA positive couple to infant,providing effective andscientific HBV prevention measures.
Methods
46families who had antenatal examination, pregnancy check-ups and gavebirth at Fujian Provincal Maternal and Child Health Hospital during August2010to November2011were chosen as research object. The information ofpregnant women，their husbands and their newborns were collected.Thosecouples’blood,hushands’sperm during pregnancy follow-up and justbefore delivery as well as their infants’ umbilical cord blood werecollected for related indicators detection.HBV serological markers wereanalysed by ELISA. HBV-DNA load and genotypes of HBV were analysed byfluorescent quantification-PCR (FQ-PCR) and type specific primers andhigh-resolution melting curve respectively.
Results
1.The positive rate of neonatal cord blood HBV-DNA was45.7%（21/46）.Univariate analysis showed that couple serum HBsAg-positiveHBVM different mode, couple serum HBeAg-positive, couple serum HBV-DNApositive，and couple serum HBV-DNA load were statistically significant(P<0.05). Using multivariate analysis to eliminate the effect ofconfounding factors, maternal serum HBV-DNA positive and paternal serumHBV-DNA load were still statistically significant(P<0.05).Maternal serumHBV-DNA positive and paternal serum HBV-DNA load did not show anyinteraction.There were dose-response relationship between couple serumHBV-DNA load level and neonatal cord blood HBV-DNA load level. The analysis of ROC curve showed that maternal serum HBV-DNA load level (1000copies/ml) and paternal serum HBV-DNA load level (10000copies/ml) werebetter demarcation point to forecast the occurrence of verticaltransmission of HBV from HBsAg or HBV-DNA positive couple toinfant,because there were better sensitivity and specificity duringforecast.
2.The maternal serum HBV-DNA load was positively correlated with thecord blood HBV-DNA load and the load level of maternal serum HBV-DNA washigher than cord blood HBV-DNA.
3.The paternal serum HBV-DNA load was positively correlated with thecord blood HBV-DNA load and the load level of paternal serum HBV-DNA washigher than cord blood HBV-DNA.
4.The paternal serum HBV-DNA load was positively correlated with semenHBV-DNA load and the load level of paternal serum HBV-DNA was higher thansemen HBV-DNA.
5. The positive rate of semen HBV-DNA was22.6%. while the positive rateof maternal serum HBV-DNA and paternal serum HBV-DNA were52.2%（24/46）and69.6%（32/46）respectively. All three were no relationships withgestational age.
6.The positive rate of cord blood HBsAg was34.8%（16/46） while thepositive rate of cord blood HBeAg was23.9%（11/46）.
7.The history of pregnancy,couple’s first class family history and HBVcarried time, liver function and neonatal outcome were no significantdifference between the case group and the control group (P>0.05).
8.23families total69portions serum samples were analysed genotype,the HBV genotype was dominant with B genotype, as well as a small amountof C genotype.9families were both couple and infant with B genotype.10families from paternal transmission included7families with Bgenotype,the else with C genotype.While4families from maternal transmission were B genotype.
9.Genotype C of paternal serum HBV-DNA load was higher than genotype B.
10. The negative conversion rate was15%(3/20) when HBV-DNA positiveinfants were followed up to7months.
Conclusion
1.Maternal serum HBV-DNA positive and paternal serum HBV-DNA load wererisk factors of vertical transmission of HBV from HBsAg or HBV-DNApositive couple to infant.
2. The couple serum HBV-DNA load was positively correlated with the cordblood HBV-DNA load and the load levels of couple serum HBV-DNA were higherthan cord blood HBV-DNA. The paternal serum HBV-DNA load was positivelycorrelated with semen HBV-DNA load and the load level of paternal serumHBV-DNA was higher than semen HBV-DNA.
3. Maternal serum HBV-DNA positive and paternal serum HBV-DNA load didnot increase the risk of vertical transmission of HBV from HBsAg or HBV-DNApositive couple to infant.
4.This study provided further evidence of vertical transmission of HBVnot only by maternal transmission,but also by paternal transmission atmolecular level. The genotype mostly were B genotype, as well as a smallamount of C genotype.
5.Genotype C of paternal serum HBV-DNA load was higher than genotype B.
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