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替诺福韦酯治疗妊娠合并慢性乙型病毒性肝炎的临床研究
The Clinical Study of Tenofovir Disoproxil in the Treatment of Pregnancy with Chronic Hepatitis B
【作者】 李娟;
【导师】 凌莉;
【作者基本信息】 苏州大学 , 妇产科学, 2019, 硕士
【摘要】 一、目的:研究妊娠合并慢性乙型病毒性肝炎于妊娠24周后应用替诺福韦酯治疗的临床疗效、母婴阻断优势及安全性。二、方法:(1)选择2015年01月~2018年05月在我院明确临床诊断为妊娠合并慢性乙型病毒性肝炎(且妊娠24周后丙氨酸氨基转移酶≥2×正常值的上限和乙型肝炎病毒e抗原(+)、乙型肝炎病毒-脱氧核糖核酸定量≥× 105IU/mL或乙型肝炎病毒e抗原(-)、乙型肝炎病毒-脱氧核糖核酸定量定量≥X 104IU/mL)并在我院分娩的95例孕妇资料进行回顾性统计分析,95例患者均在发现肝功能异常后常规使用保肝药物(复方甘草酸制剂、还原型谷胱甘肽、多烯磷脂酰胆碱中的1种)保肝治疗,服用至肝功能正常后停药;由于经济条件、文化水平及对疾病认知程度的差异,其中45例孕妇接受自妊娠24周后开始加服替诺福韦酯(300mg/d)抗病毒治疗,并服用至分娩后6周,依据所复查的肝功能及病毒学指标的结果决定停药或转诊至肝病科继续治疗,被纳入研究组。与研究组同期有50例孕妇拒绝服用替诺福韦酯治疗,继续单独使用保肝药物治疗,被纳入对照组。(2)通过监测两组孕妇治疗前、治疗4周、8周、产时及产后6周的病毒血清学、生化学指标的变化,并且与同期对照组比较母儿并发症的差异、药物本身的不良反应来探讨妊娠24周后开始口服替诺福韦酯对合并慢性乙型病毒性肝炎孕妇的治疗效果及安全性;同时,两组孕妇共分娩95例胎儿,研究组活产45例;对照组活产49例,死胎1例。两组新生儿85例出生后接受0、1、6月乙肝疫苗10ug和0、1月乙肝免疫球蛋白100IU注射联合免疫预防处理,积极配合随诊至7月龄。9例早产儿推迟注射乙肝免疫球蛋白至1月龄。抽取两组孕妇所分娩的94例新生儿的脐带血及出生7月龄的婴儿的外周血,通过比较这两组血乙型肝炎病毒-脱氧核糖核酸定量定量及乙肝表面抗原的阳性率来探讨替诺福韦酯用于母婴阻断的优势。(3)统计方法:所有数据应用SPSS19.0软件进行统计学分析,正态分布资料,计量数据以均数±标准差(x±s)表示,组间比较采用t检验;非正态分布数据,则计量数据以中位数(25%、75%四分位数)表示,两组间比较采用非参数检验(秩和检验);计数数据,由频数,构成比或率表示,组间比较采用卡方检验,检验水准α=0.05。三、结果(1)在年龄、体重指数、地理分布、孕产史、发现肝功能异常孕周、治疗前血清丙氨酸氨基转移酶(Alanine aminotransferase,ALT)、血清天门冬氨酸氨基转移酶(Aspartate transaminase,AST)、总胆红素(Total bilirubin,TBiL)、白蛋白(Albumin,ALB)、胆碱醋酶(Choline esterase,CHE)、血清尿素氮(Blood urea nitrogen,BUN)、肌酐(Creatinine,CR)、磷(Phosphorus,P)、血红蛋白(Hemoglobin,HB)浓度、全血白细胞(White blood cell,WBC)、血小板(Platelet,PLT)计数、血浆凝血酶原时间(Prothrombin time,PT)、血清乙型肝炎病毒-脱氧核糖核酸(Hepatitis B virus-Deoxyribonucleic acid,HBV-DNA)定量、乙型肝炎病毒 e 抗原(Hepatitis B virus E antigen,HbeAg)定量检测值,两组研究对象均无统计学差异,提示两组资料具有可比性;但两组患者在文化水平差异上有统计学意义。(2)研究组孕妇在治疗4周、治疗8周、产时及产后6周时HBV-DNA阴转(HBV-DNA 定量<100IU/mL)率分别为 4.44%,8.89%,17.78%,24.44%,而对照组均为0%;治疗8周始研究组的HBV-DNA阴转率与对照组相比有统计学差异。研究组治疗4周时孕妇HBV-DNA定量即下降近31og10IU/mL,治疗8周时下降近5 logioIU/mL,与基线水平相比差异有统计学意义。(3)研究组孕妇在治疗4周、治疗8周、产时及产后6周时ALT复常(ALT浓度<40U/L)率分别为20%,33.33%,66.67%,73.33%,而对照组ALT复常率分别为26%,32%,44%,50%;治疗至产时两组ALT复常率的差异具有统计学意义。(4)两组新生儿出生时脐静脉血及出生7月龄的婴儿外周血HBV-DNA阳性率,研究组为0%,0%,对照组为100%、12.24%,两组差异有统计学意义;HBsAg 阳性率,研究组为8.88%,0%,对照组为100%、12.24%,两组差异有统计学意义。(5)血清ALT浓度变化比较:研究组与基线水平比较虽有一过性升高,但总体呈下降趋势,且至产时下降的程度具有统计学意义。血清AST浓度变化比较:研究组至产时与基线水平比较出现的下降,有统计学意义,对照组则在产后6周与基线水平比较出现的下降,有统计学意义。血清TBiL浓度变化比较:研究组在治疗8周与基线水平比较出现的下降有统计学意义,对照组则在产后6周与基线水平比较出现的下降,有统计学意义。血清ALB、CHE、BUN、CR、P、HB浓度、全血WBC、PLT计数:两组比较均无统计学差异。血浆PT:对照组于产时及产后6周的凝血酶原时间均较治疗前延长,且两组间同期对比有明显统计学差异。(6)研究组的平均分娩孕周明显高于对照组;研究组的早产率明显低于对照组;两组差异均有统计学意义。而研究组的产后出血发生率、胎膜早破发生率、并发妊娠期高血压疾病率及剖宫产率低于对照组,但差异无统计学意义。研究组新生儿窒息率、低出生体重率、死胎引产率、新生儿病理性黄疸发生率、转诊NICU率及出生缺陷率之间的比较无统计学差异。(7)两组孕妇发生的药物本身的不良反应症状均轻微,无1例严重不良事件发生,所娩新生儿研究组无先天性畸形发生,对照组2例出生缺陷,两组比较,差异无统计学意义。四、结论对妊娠合并慢性乙型病毒性肝炎孕妇24周后采用替诺福韦酯抗病毒治疗,对提高母婴阻断的成功率有较强的优势,同时对母体的肝功能的恢复,延缓肝纤维化的进展具有临床价值,药物的不良反应少,且从经济层面分析,使用替诺福韦酯抗病毒治疗可缩短住院时长并减少住院费用,值得临床应用和推广。
【Abstract】 Objective:To study the clinical efficacy,maternal and infant blockade and safety of Tenovir dipivoxil in pregnant women with chronic hepatitis B after 24 weeks of gestation.Methods:(1)Choose the time from January 2015 to May 2018 in my hospital to clearly diagnose the clinical diagnosis of chronic hepatitis B(and after 24 weeks of pregnancy alanine transferase≥2×the upper limit of normal values and HbeAg(+),HBV-DNA quantification≥×105 IU/mL or HBeAg(-),HBV-DNA quantification≥×104 IU/mL)and 95 cases of pregnant women delivered in our hospital for retrospective statistical analysis,95 patients routinely used anti-inflammatory and hepatoprotective drugs for hepatoprotective treatment after the abnormal liver function was found(one of the compound glycyrrhizic acid preparation,reduced glutathione and polyene phosphatidylcholine)were routinely used for hepatoprotective treatment,and the drug was stopped after the liver function was normal.Due to the economy conditions,cultural level and differences in awareness of the disease,45 pregnant women received anti-viral treatment with tenofovir(300 mg/d)from the 24th week after pregnancy,and taken to 6 weeks after delivery,according to the institute.The results of the review of liver function determine the withdrawal or referral to the liver Section to continue treatment,and signed informed consent were included in the study group.In the same period of the study group,50 pregnant women refused to take Tenofovir.They continued to receive anti-inflammatory and hepatoprotective drugs alone,were included in the control group,and signed the refusal to take Tenofovir.(2)By monitoring the changes in serum serology and biochemical indicators of the two groups of pregnant women before treatment,treatment at 4 weeks,8 weeks,delivery time and 6 weeks postpartum,and comparing the differences in maternal and child complications with the control group,the drug itself.The adverse reactions were to investigate the efficacy and safety of oral Tenofovir dipivoxil in pregnant women with chronic hepatitis B after 24 weeks of gestation.At the same time,95 pregnant fetuses were delivered in the two groups,and 45 live births in the study group.The control group had 49 live births and 1 stillbirth.The peripheral blood of 94 newborns born to pregnant women and the 7-month-old infants were drawn.The positive rate of HBV-DNA and HBsAg in the two groups was compared to investigate the use of Tenofovir and the advantage of blocking.(3)Statistical methods:normal distribution data,measurement data are expressed as mean ± standard deviation(x ± s),t-test is used for comparison between groups,non-normal distribution data,the measurement data is median(25%),75%quartile distance),the inter-group analysis adopts the rank sum test.The count data is represented by the number of cases and/or the rate,and the chi-square test is performed.All the data are processed by SSPS19.0 statistical software,P<0.05 indicates that the difference has Statistical significance.Results(1)Age,body mass index,geographical distribution,maternal history,abnormal liver function found,pre-treatment serum ALT,AST,TBiL,ALB,CHE,BUN,CR,P,HB concentration,whole blood WBC,PLT Counting,plasma PT,serum HBV-DNA quantification,and HBeAg quantitative detection values were not statistically different between the two groups,suggesting that the data were comparable between the two groups.However,the difference between the two groups was statistically significant.(2)The HBV-DNA negative conversion rate of pregnant women in the study group was 4.44%,8.89%,17.78%,24.44%,respectively,at 4 weeks of treatment,8 weeks of treatment,and at 6 weeks postpartum,while the control group was 0%.The rate of HBV-DNA negative conversion(HBV-DNA quantification<100 IU/mL)in the study group at the 8th week of treatment was statistically different from that of the control group.The HBV-DNA quantification of the pregnant women in the study group decreased by nearly 3 log10 IU/mL at 4 weeks of treatment,and decreased by nearly 5 log10 IU/mL at 8 weeks of treatment.The difference was statistically significant compared with the baseline level,but there was no change in the control group.(3)The ALT recurrence(ALT concentration<40U/L)rate of the pregnant women in the study group was 20%,33.33%,66.67%,and 73.33%,respectively,at 4 weeks of treatment,8 weeks of treatment,and at 6 weeks postpartum.The ALT recurrence rate was 26%,32%,44%,and 50%,respectively.The difference in ALT recurrence rate between the two groups was statistically significant.I(4)The positive rate of HBV-DNA in peripheral blood of newborns at the time of birth and the 7-month-old infants in the two groups were 0%,0%in the study group and 100%and 12.24%in the control group.Significance,HBsAg positive rate,the study group was 8.88%,0%,the control group was 100%,12.24%,the difference between the two groups was statistically significant.(5)Comparison of serum ALT concentration changes:although the study group had a transient increase compared with the baseline level,the overall trend showed a downward trend,and the degree of decline to the time of birth was statistically significant.The control group also showed a certain degree compared with the baseline level.The degree of decline,but not statistically significant.Comparison of serum AST concentration changes:the decrease in the study group to the baseline and the baseline level was statistically significant.The control group showed a statistically significant decrease from the baseline level at 6 weeks postpartum.Serum TBiL concentration changes:the study group showed a statistically significant decrease in baseline compared with baseline at 8 weeks of treatment,and the control group showed a statistically significant decrease from baseline at 6 weeks postpartum.Serum ALB,CHE,BUN,CR,P,HB concentration,whole blood WBC,PLT count:there was no statistical difference between the two groups.Plasma PT:the prothrombin time of the control group at the time of delivery and 6 weeks postpartum was longer than that before the administration,and there was a statistically significant difference between the two groups.(6)The average gestational age of the study group was significantly higher than that of the control group.The preterm birth rate of the study group was significantly lower than that of the control group.The difference between the two groups was statistically significant.The incidence of postpartum hemorrhage,premature rupture of membranes,concurrent gestational hypertension,and cesarean section rate in the study group were lower than those in the control group,but the difference was not statistically significant.There was no significant difference between the study group’s neonatal asphyxia rate,low birth weight rate,stillbirth rate,neonatal pathological jaundice,referral NICU rate and birth defect rate.(7)The adverse reactions of the drugs in the two groups of pregnant women were mild,and no serious adverse events occurred.ConclusionsAnti-viral treatment with Tenofovir disoproxil in pregnant women with chronic hepatitis B after 24 weeks has a strong advantage in improving the success rate of maternal and child blockade,while restoring the liver function of the mother,delaying liver fiber The progress of chemotherapy has clinical value,the adverse reactions of drugs are few,and from the economic analysis,the anti-viral treatment with Tenofovir can shorten the length of hospital stay and reduce the hospitalization cost,which is worthy of clinical application and promotion.
【Key words】 Chronic hepatitis B; Antiviral therapy; Tenofovir disoproxil; Maternal and child block;