慢性乙型肝炎病毒感染母亲母乳喂养婴儿乙型肝炎病毒表面抗体水平监测及临床意义

Monitoring on hepatitis B virus surface antibody level of breastfeeding infants of mothers with chronic hepatitis B virus infection and its clinical significance

目的探讨慢性乙型肝炎病毒(HBV)感染母亲母乳喂养婴儿的乙型肝炎病毒表面抗体(HBsAb)水平检测对评估母乳喂养安全性的意义。方法选取2017年12月至2018年12月出生于首都医科大学附属北京地坛医院并接受HBV母婴垂直传播免疫阻断的婴儿213例为研究对象。HBV母婴垂直传播免疫阻断方法为新生儿于出生后24 h内注射人乙肝免疫球蛋白(100 IU),同时在不同部位接种重组人乙肝疫苗(10μg),并分别于1月龄、6月龄于三角肌接种乙肝疫苗(10μg)。分别于婴儿出生后24 h内、出生后42 d、3月龄、7月龄和12月龄抽取静脉血,检测血清HBsAb和HBV DNA载量。采用非参数检验Kruskal-Wallis H(K)和秩和检验比较不同时间点HBsAb水平差异,卡方检验比较乙肝疫苗免疫无/低应答的比率。结果入组213例婴儿平均胎龄为(38.72±1.20)周,出生平均体重为(3.29±0.39)kg;自然分娩151例(70.89%),剖宫产62例(29.11%);母亲乙型肝炎病毒e抗原(HBe Ag)阳性75例(35.21%),孕28周HBV DNA载量>2×105 IU/ml者90例(42.25%),孕期行抗病毒治疗者109例(51.17%)。婴儿出生时、出生后42 d、3月龄、7月龄和12月龄的HBs Ab分别为0.5(0.31,0.92)mIU/ml、247.76(232.99,294.49)mIU/ml、163.3(105.85,311.59)mIU/ml、1000(887.56,1000)mIU/ml和239.99(106.76,515.90)mIU/ml,各时间点整体差异有统计学意义(Z=308.51、P<0.001),每个时间点较前一个时间点差异均有统计学意义(42 d vs.出生时:Z=-7.09、P<0.001,3个月vs.42 d:Z=-3.23、P=0.001,7个月vs.3个月:Z=-14.32、P<0.001,12个月vs.7个月:Z=-12.00、P<0.001)。婴儿出生后42 d、3月龄、7月龄和12月龄发生乙肝疫苗免疫无/低应答的比率分别为1.88%(4/213)、42.72%(91/213)、3.76%(8/213)和24.41%(52/213),各时间点整体差异有统计学意义(χ^(2)=159.58、P<0.001),每个时间点较前一个时间点差异均有统计学意义(3个月vs.42 d:χ^(2)=102.54、P<0.001,7个月vs.3个月:χ^(2)=90.65、P<0.001,12个月vs.7个月:χ^(2)=37.56、P<0.001)。3月龄和7月龄分别有2例和1例婴儿血清HBV DNA阳性,该3例HBV DNA阳性婴儿均存在免疫低应答,HBV DNA阳性婴儿发生免疫无/低应答的比率较HBV DNA低于检测下限婴儿差异无统计学意义(Fisher’s确切概率法检验:P=0.18、0.24),可能与本研究样本量较少有关。结论HBV感染母亲婴儿母乳喂养期间HBsAb波动较大,3月龄和12月龄婴儿发生乙肝疫苗免疫无/低应答的比率较高,应加强监测以保证母乳喂养的安全性。

Objective To explore the significance of monitoring hepatitis B surface antibody(HBs Ab)level in infants of mothers with chronic hepatitis B virus(HBV)infection and to assess the safety of breastfeeding.Methods Total of 213 infants of mothers with HBV infection from December 2017 to December 2018 in Beijing Ditan Hospital,Capital Medical University were enrolled,who received immunization program of HBV mother-to-child transmission blockade.The measures of HBV mother-to-child transmission blockade included injection of hepatitis B virus immune globulin(100 IU)and recombinant hepatitis B virus vaccine(10μg)at different sites within 24 hours after birth,and immunization with hepatitis B virus vaccine(10μg)at one month and six months,respectively.The levels of HBsAb and HBV DNA of venous blood were detected among the enrolled infants within 24 hours,42 days,3 months,7 months and 12 months after birth.The levels of HBsAb at different time points were analyzed by non-parametric tests for Kruskal-Wallis H(K)and ranksum test;the ratio of non/low response to hepatitis B vaccine immunity at different time points were compared by Chi-square test.Results The average gestational age of 213 infants was(38.72±1.20)weeks,the mean birth weight was(3.29±0.39)kg,there were 151(70.89%)cases with natural birth,62(29.11%)cases with cesarean section,75(35.21%)cases with positive maternal hepatitis B virus e antigen(HBeAg),90(42.25%)cases with HBV DNA load>2×105 IU/ml at 28 weeks,and 109(51.17%)cases underwent antiviral treatment during pregnancy.The levels of HBsAb at birth,42 days,3 months,7 months and 12 months after birth were 0.5(0.31,0.92)mIU/ml,247.76(232.99,294.49)mIU/ml,163.3(105.85,311.59)mIU/ml,1000(887.56,1000)mIU/ml and 239.99(106.76,515.90)mIU/ml,respectively.The overall difference between each time point was significantly different(Z=308.51,P<0.001);and each time point was statistically different from the previous time point(42 days vs.at birth:Z=-7.09,P<0.001,3 month vs.42 d:Z=-3.23,P=0.001,7 months vs.3 months:Z=-14.32,P<0.001;12 months vs.7 months:Z=-12.00,P<0.001).The rates of non/low response to hepatitis B virus vaccine at 42 days,3 months,7 months and 12 months after birth were 1.88%(4/213),42.72%(91/213),3.76%(8/213)and 24.41%(52/213),respectively,the overall difference between each time point was significantly different(χ^(2)=159.58,P<0.001),the difference at each time point was statistically significant from the previous time point(3 months vs.42 days:χ^(2)=102.54,P<0.001,7 months vs.3 months:χ^(2)=90.65,P<0.001;12 months vs.7 months:χ^(2)=37.56,P<0.001).Two infants at 3 months and one infant at 7 months with HBV DNA positive all had low response to hepatitis B virus vaccine.The ratio of non/low response to hepatitis B virus vaccine immunity between infants with HBV DNA positive and with HBV DNA lower than the lowest limit at 3 months and 7 months old were significantly different(Fisher’s exact probability test:P=0.18,0.24),which may be related to the small sample size.Conclusions HBsAb fluctuates greatly during breastfeeding of HBV-infected mother’s infants,and the rates of non/low-response status at 3 months and 12 months after birth were high,and monitoring of HBsAb levels should be strengthened to ensure the safety of breastfeeding.