阻断乙型肝炎病毒母婴传播的相关研究进展

乙型肝炎（简称乙肝）病毒母婴传播是乙肝主要传播途径。母婴传播主要见于高病毒载量和乙肝e抗原阳性的孕妇。对这些孕妇孕晚期给予抗病毒治疗,联合新生儿和婴儿及时规范全程接种乙肝免疫球蛋白和乙肝疫苗,以尽最大可能阻断母婴传播。本文对孕期抗病毒药物用药、停药和产后乙肝发作处理、母乳喂养问题进行综述,以进一步优化联合免疫接种和抗病...     

产科消除母婴传播门诊建设在妇幼专科医院的价值

母婴传播是乙肝传播的主要方式之一,目前联合免疫是阻断乙肝母婴传播的最有效方法,但仍有8%～15%孕妇所生婴儿中存在预防接种无效,发生乙肝母婴传播,孕妇外周血中乙肝病毒(HBV)DNA载量是乙肝母婴传播的独立危险因素。目前国内外推荐妊娠晚期服用抗病毒药物减少母婴传播,但因大部分产科医务工作者未充分认识,仅少部分对乙肝孕妇进行处理并及时转诊至肝病科或感染科就诊治疗。此外,孕妇孕期多机构、多科室就诊非常不便利,并且获得信息不对称,多次就诊潜在增加乙肝相关羞辱歧视的风险,特别是对于没有肝病科或感染科的妇幼保健专科医院,如何处理管理这一人群成为难点。消除母婴传播(E)门诊的建立可健全消除母婴传播服务能力,通过整合艾梅乙患者孕期管理,为感染孕产妇提供标准化的全流程一站式服务,从而有效减少乙肝母婴传播发生。     

妊娠晚期注射乙肝免疫球蛋白无助于阻断乙型肝炎病毒母婴传播

母婴传播是乙型肝炎病毒(hepatitis B virus,HBV)感染的主要途径之一.既往有学者报道,妊娠晚期注射乙肝免疫球蛋白(hepatitis B immunoglobulin,HBIG)可降低HBV母婴传播率[1,2],但亦有学者提出异议[3],认为妊娠期使用HBIG不能降低孕妇病毒载量,对阻断HBV母婴传播无效[4,5].本研究分析了538例妊娠晚期使用HBIG和817例妊娠期未使用HBIG的HBV携带孕妇及其新生儿资料,旨在探讨妊娠期使用HBIG阻断HBV母婴传播的效果,现将结果报道如下.     

孕妇产前进行免疫阻断与新生儿乙型肝炎基因疫苗免疫效果关系的研究

目的探讨采用乙型肝炎免疫球蛋白(HBIG)阻断孕妇乙型肝炎病毒(HBV)感染对新生儿乙型肝炎(简称乙肝)基因疫苗免疫效果的影响。方法对55例HBV标志物阳性孕妇于产前28周、32周和36周分别给予HBIG 200IU免疫阻断作为阻断组；31例HBV标志物阳性孕妇未给予HBIG免疫阻断作为未阻断组；同期选择HBV标志物阴性孕妇42例作为对照组。对三组新生儿分别给予乙肝基因疫苗的免疫接种，并分别于1个月、2个月、7个月和12个月龄采集外周血检测HBV标志物及丙氨酸转氨酶(ALT)。结果阻断组、未阻断组和对照组新生儿免疫保护率分别为87.3%(48/55)、77.4%(24/31)和97.6%(41/42)；未阻断组与对照组间比较具有统计学意义(P<0.01)；对“大三阳”孕妇的阻断效果最好，新生儿抗HBs阳转率从33.3%上升到71.4%。结论对HBV感染孕妇采用HBIG免疫阻断，可以降低宫内感染及母婴传播的发生率；分娩时孕妇HBV感染状态对新生儿抗HBs阳转率可能产生一定程度的影响。     

产前抗病毒治疗对于阻断乙肝病毒母婴垂直传播作用的Meta分析

目的:评价乙肝病毒感染者孕期抗病毒治疗的疗效,探讨产前抗病毒治疗的指征。方法:对国内外12篇有关产前抗病毒治疗阻断乙肝母婴传播的文献进行Meta分析。结果:抗病毒治疗组婴儿出生时HBs Ag阳性的风险比对照组减少63%(RR=0.37,95%CI为0.22~0.62,P=0.0001),其中乙肝病毒载量≥106拷贝/ml组婴儿出生时HBsAg阳性风险减少76%(RR=0.24,95%CI为0.08~0.67,P=0.007);抗病毒治疗组婴儿6~12月龄HBsAg阳性的风险比对照组减少83%(RR=0.17,95%CI为0.11~0.27,P0.00001),其中乙肝病毒载量≥106拷贝/ml组婴儿6~12月龄HBsAg阳性风险减少89%(RR=0.11,95%CI为0.05~0.23,P0.00001);经抗病毒治疗后孕妇血清HBV DNA水平明显降低(SMD=-3.67,95%CI为-4.52~-2.82,P0.00001)。结论:产前抗病毒治疗可降低乙肝病毒感染者分娩前HBV DNA水平,其中乙肝病毒载量≥10~6拷贝/ml时抗病毒治疗,能有效阻断乙肝病毒母婴垂直传播。     

乙型肝炎病毒DNA检测在孕期的应用

孕妇血清乙型肝炎病毒(hepatitis B virus, HBV)DNA水平目前被认为是预测发生HBV母婴垂直传播的一个最重要指标和独立的危险因素。普遍认为,在充分考虑对孕妇及胎儿的利与弊的前提下,妊娠中、晚期口服安全性较高的核苷(酸)类抗病毒药物,可在分娩前明显降低母血中HBV DNA载量,从而最大程度地阻断HBV母婴垂直传播。抗病毒治疗4周后监测HBV DNA载量可以预估核苷(酸)类药物抗病毒治疗的远期有效性,以便及时调整治疗方案。HBV DNA检测在孕期的应用与何时应用对阻断HBV母婴垂直传播具有重要意义。     

乙肝母婴传播阻断的健康教育干预分析

目的分析乙肝母婴传播阻断的健康教育干预。方法回顾性分析我院2014年2月~2015年1月收治的乙肝孕妇临床资料120例,根据不同护理模式分为两组,各60例,对照组予常规护理,研究组辅以健康教育干预,观察并比较两组婴儿不同月龄HBs Ag、抗-HBs阳性率、孕妇疾病知晓情况及护理满意度。结果研究组新生儿于0月龄与6月龄时HBs Ag阳性率1.67%、1.67%,均显著低于照组16.67%、15.00%,差异有统计学意义(P0.05);研究组乙肝母婴传播阻断知识知晓率均比对照组高,且护理满意率研究组91.67%比对照组的61.67%高,差异有统计学意义(P0.05)。结论健康教育干预应用于乙肝母婴传播阻断的效果良好。     

佛山市乙型肝炎母婴阻断工作环节问题探讨

目的探讨佛山市乙肝母婴阻断工作中存在的问题,为完善进一步工作提供思路。 方法采用队列研究的方法,以2017年佛山市HBsAg阳性产妇13 672例及其所分娩13 982例活产儿为研究对象,通过回顾性病历采集及前瞻性的随访追踪的方法,全面了解影响乙肝母婴阻断工作的主要因素。 结果2017年佛山市产妇HBsAg阳性率为10.14%,感染孕妇中HBeAg阳性率为24.13%,孕期HBV DNA检测率约5%,其中抗病毒治疗63例;新生儿乙肝免疫球蛋白接种率为99.84%;婴儿在出生后1年内完成乙肝疫苗三针接种的比率为81.71%,在完成三针乙肝疫苗接种的儿童中按照0-1-6程序接种的比率为62.65%;母婴阻断结果追踪率为40.16%,追踪儿童中母婴阻断失败34例,失败率为0.61%;产妇年龄低、HBeAg阳性、HepB未全程及规范接种是母婴阻断失败的危险因素(P<0.05)。儿童明确未检测的主要原因是拒绝检查、不知道要检查、提前检查和检测未提供结果,占99.07%。 结论加强信息沟通及健康教育,落实乙肝病毒感染产妇孕期DNA检测及抗病毒治疗,提高儿童乙肝疫苗的规范接种率,将暴露儿童的乙肝两对半检测纳入儿童保健管理工作,是实现全市乙肝母婴零传播的重要措施。     

乙型肝炎母婴传播现状及预防策略

预防乙型肝炎(乙肝)病毒母婴传播是控制慢性乙肝的关键。对所有乙肝表面抗原阳性母体的子代及时联合免疫预防,同时建议高病毒水平(HBV DNA>2×10⁵U/mL)或乙肝e抗原阳性孕妇晚孕期服用抗病毒药物,母婴传播率可降至0.2%以下。全国普遍严格落实这些措施,是消除慢性乙肝的关键。     

131例乙肝孕妇行介入性产前诊断的垂直传播风险分析

目的了解行介入性诊断的乙肝孕妇发生垂直传播的风险情况。方法回顾性分析2017年7月至2018年6月间来广东省妇幼保健院产前诊断科行介入性产前诊断、符合纳入标准的乙肝表面抗原(HBsAg)阳性孕妇及其所生婴儿的临床资料,总结不同穿刺类型、不同穿刺指征、是否合并乙肝e抗原(HBeAg)阳性等情况下的母婴垂直传播风险。结果本研究共纳入131例(含双胎5例)乙肝孕妇和136例所生婴儿,共3例(2.21%)在乙肝联合免疫后依然被检出感染乙肝;HBeAg阴性和HBeAg阳性孕妇所生婴儿发生感染的几率分别为1.09%(1/92)和5.71%(2/35);乙肝病毒DNA定量超过106IU/ml和107IU/ml的垂直传播率分别为4.35%(1/23)和5.00%(1/20);行羊膜腔穿刺术、脐静脉穿刺术和绒毛吸取术的乙肝孕妇发生垂直传播的几率分别为1.11%(1/90)、2.56%(1/39)和14.29%(1/7);因超声异常表现和其他非超声异常指征行介入性产前诊断孕妇发生垂直传播的风险分别为2.82%(2/71)和1.54%(1/65);10例孕妇孕期接受了抗病毒治疗,该10例所生婴儿均未发生感染。结论乙肝孕妇行介入性产前诊断有发生母婴垂直传播的风险,仍需大样本研究进一步探讨。     

乙型肝炎女性围产期管理

虽然乙型肝炎（乙肝）疫苗联合乙肝高效价免疫球蛋白的免疫可以有效地预防围产期和幼儿期乙肝感染,但我国每年约有（12~17）万儿童因免疫失败成为慢性乙肝病毒感染者。因此,对乙肝女性的孕前、孕期及产后进行规范化管理,从源头上阻断乙肝母婴传播,将宫内感染和新生儿感染风险降到最低是当务之急。文章结合我国及国外最新指南,对乙肝女性围产期的预防和管理进行总结和概述。     

Hepatitis B—management of acute infection and active inflammation in pregnancy—a hepatologist's perspective

Women at childbearing age and pregnant ladies living in the areas of high or intermediate prevalence of hepatitis B virus (HBV) remain at risk of getting the infection and passing the infections to their offspring via mother-to-child transmission (MTCT) of HBV. HBV infection may affect the mothers by active hepatitis, very occasionally liver cirrhosis and rarely fulminant hepatitis and liver failure. The virus may be transmitted to the babies despite immunoprophylaxis in the setting of very high maternal viral load. Tenofovir disoproxil fumarate (TDF) has been shown to be efficacious to reduce MTCT of HBV, which contributes to the elimination of chronic HBV infection by 2030, the goal set by World Health Organization.     

Preventing Neonatal Hepatitis B Infection During the Perinatal Period

In the United States, hepatitis B virus (HBV) infection is a growing problem with serious long-term consequences. Because previous vaccination programs have been ineffective in lowering the incidence of HBV, the U.S. Centers for Disease Control now recommend a comprehensive plan to reduce transmission of the virus. This article explores the epidemiology of HBV infection, the use of hepatitis B immune globulin and hepatitis B vaccines, and current recommendations for eliminating transmission of HBV during the perinatal period.     

Chronic hepatitis B infection and pregnancy

It is estimated that 350 to 400 million individuals worldwide are chronically infected with hepatitis B virus (HBV). In regions of high endemicity, many of these are females of reproductive age who are an important source for perinatal transmission. There are a number of issues specific to the women of childbearing age who have chronic HBV infection, including the safety of antiviral therapy during pregnancy and breast-feeding, the changes in the immune system during pregnancy and postpartum that may impact on the natural history of HBV, and the emerging role of antivirals to reduce perinatal transmission of HBV. For women in their reproductive years who require treatment, many of the available antivirals have not been studied in pregnant or breast-feeding women and their use requires the development of a carefully considered strategy, considering the impact of both the disease and treatment on the mother and fetus/infant. The purpose of this article is to (1) review data regarding the mechanisms and timing of perinatal HBV infection; (2) review data on interventions, particularly antiviral therapy, to reduce perinatal transmission beyond the protection afforded by hepatitis B immunoglobulin and vaccination; (3) summarize the immunological changes associated with pregnancy and the potential effect these may have on the natural history of HBV infection; and (4) summarize the information currently available for antiviral therapy available for HBV treatment, focusing specifically on safety data pertaining to reproduction, pregnancy, and breast-feeding. TARGET AUDIENCE: Obstetricians & Gynecologists and Family Physicians. LEARNING OBJECTIVES: After completing this CME activity physicians should be better able to classify the interventions to reduce mother-to-child transmission of hepatitis B including antivirals, caesarean section, hepatitis B immunoglobulin and hepatitis B vaccine, assess the immunological changes associated with pregnancy and the potential effect this may have on the natural history of HBV infection and apply the information currently available for antiviral therapy licensed for HBV treatment, focusing specifically on safety data in pregnancy and during breastfeeding.     

Towards complete eradication of hepatitis B infection from perinatal transmission: review of the mechanisms of in utero infection and the use of antiviral treatment during pregnancy

Hepatitis B infection remains the most common form of chronic hepatitis. Mother to child transmission occurs despite immunoprophylaxis with vaccination and immunoglobulin. In utero infection is suggested to account for most of the cases with immunoprophylaxis failure. Infants who suffer from hepatitis B infection at birth have a higher risk of becoming chronic carriers and may develop liver cirrhosis or hepatocellular carcinoma in the future. Infected germ cells, transplacental infection, invasive prenatal diagnostic tests and various perinatal factors are possible factors leading to in utero infection and subsequent immunoprophylaxis failure. Hepatitis B e antigen positive status and high viral load increase the risk of immunoprophylaxis failure. Recent evidence shows promising results regarding the use of antiviral treatment in late gestation to suppress viral load, so as to decrease the risk of vertical transmission. This review discusses the possible mechanisms of in utero infection and the use of antiviral treatment during pregnancy.     

常规免疫预防阻断乙型肝炎病毒母婴感染的效果

目的 评价免疫预防措施在实际应用中阻断乙型肝炎病毒(hepatitis B virus,HBV)母婴感染的效果,阐明孕妇孕晚期使用乙肝免疫球蛋白(hepatitis B immunoglobulin,HBIG)能否减少HBV母婴感染.方法 将2002年7月至2004年8月江苏省14个县市的419例乙型肝炎表面抗原(hepatitis B surface antigen,HBsAg)阳性孕妇所分娩子女作为研究组,同地区同期的453例 HBsAg-孕妇分娩的子女作为对照组,于2009年10月至2010年3月期间对2组研究对象进行随访,调查母亲孕期HBIG使用情况以及子女出生后HBIG和乙型肝炎疫苗接种情况,检测儿童HBV血清标志物.率的比较采用χ2分析或者Fisher精确概率法,均数的比较采用t检验.结果研究组实际随访298例(71.12%),其中11例(3.69%) HBsAg+;而随访的328例(72.41%)对照组中,HBsAg阳性率为0.00 (χ2=12.32,P<0.01).共11例儿童HBsAg+,其母亲均为HBsAg和HBeAg同时阳性,除1例具体情况不详外,9例儿童在出生时明确没有使用HBIG或延迟接种疫苗,仅1例同时规范使用了HBIG和乙型肝炎疫苗.2组儿童抗-HBs阳性率分别为69.46%和69.21% (χ2=0.01,P=0.95).孕晚期注射HBIG的92例孕妇中,2例(2.17%)儿童HBsAg+;未使用HBIG的197例孕妇中,9例(4.57%)儿童HBsAg+ (χ2=0.98,P=0.51).结论 江苏省常规免疫预防措施在阻断母婴HBV感染方面取得了良好的效果,但对HBV携带孕妇(特别是HBeAg+者)的新生儿仍需强调及时注射HBIG.孕妇孕晚期使用HBIG不能减少母婴HBV感染.

Abstract：

Objective To assess the protective effect of vaccination in routine application on hepatitis B virus (HBV) exposed infants and to clarify whether hepatitis B immunoglobulin (HBIG) administration of pregnant women may reduce the risk of maternal-fetal transmission of HBV. Methods Serum samples of 6398 pregnant women at gestation of 15-20 weeks from 6 urban and 8 rural areas across Jiangsu province were previously tested for serologic markers of HBV by ELISA from July 2002 to August 2004. In this study, infants born to 419 HBV carrier mothers were taken as the study group, while infants born to 453 non-carrier mothers were taken as the control group by stratified random sampling. They were followed-up and screened for HBV markers during October 2009 to March 2010. Information including HBIG administration during pregnancy, HBV vaccination and HBIG administration of the infants were collected. χ2 test or Fisher′s exact method were used to compare the rates and the comparison of the means was by t test. Results The follow-up rates of the study group and control group were 71.12% (298/419) and 72.41% (328/453), respectively. Of the 298 infants born to HBV carrier mothers, 11 (3.7%) were positive for HBsAg, while none of the 328 infants born to non-carrier mothers was HBsAg positive (χ2=12.32, P<0.01). All of the 11 children were born to mothers with both HBsAg and HBeAg positive, and nine of the 11 children were not injected HBIG or not immunized with hepatitis B vaccine within 24 hours after birth, with only one received regular vaccination and detailed information was unknown in one case. The positive rates of anti-HBs in the study group and the control group were 69.46% and 69.21% respectively (χ2=0.01, P=0.95). HBsAg positive rate of the children born to pregnant women treated with HBIG during late pregnancy (n=92) was 2.17% (n=2), whereas that in the children born to women not treated with HBIG (n=197) was 4.57% (χ2=0.98, P=0.51). Conclusions The protective effect of immunoprophylaxis in routine application against perinatal HBV infection in Jiangsu province is good. Efforts are required to emphasize the importance of HBIG administration in infants born to HBV carrier mothers, especially in HBeAg positive mothers within 24 hours after delivery. Treatment of HBsAg positive pregnant women with HBIG in third trimester would not decrease the risk of maternal-fetal transmission of HBV.     

Hepatitis B – chronic carrier status and pregnancy outcomes: An obstetric perspective

Antenatal screening for hepatitis B surface antigen (HBsAg) only identifies women with hepatitis B virus (HBV) infection for neonatal immunoprophylaxis. It does not reflect the phase of chronic infection, viral genotype and activity, hepatic inflammation, or other co-existing liver disorders. Coinfection with other viruses and micro-organisms may also be present. These factors in various combinations can impact pregnancy outcomes, and they are probably responsible for the conflicting literature on this issue. Pregnancy complications may interact with maternal HBV infection and hepatitis flares, leading to serious and lethal complications. Hepatitis flares are common especially postpartum, and they are unpredictable and unpreventable with antiviral treatment. Evidence on the association between HBsAg seropositivity with gestational diabetes mellitus, preterm birth, increased foetal growth, and reduced pregnancy hypertensive disorders is stronger than other adverse pregnancy outcomes. Baseline assessment of liver function, and viral markers and activity, can delineate the truly high-risk pregnancies for close monitoring.     

妊娠合并乙型肝炎病毒感染孕妇胎儿窘迫发病原因分析

目的：探讨妊娠合并乙型肝炎病毒（HBV）感染孕妇胎儿窘迫的病因、预后及治疗方法。方法：对81例妊娠期HBV表面抗原（HBsAg）、HBVe抗原（HBeAg)、HBV核心抗体（HBcAb)和HBV DNA均阳性,肝功能正常的孕妇及其新生儿（研究组）,85例无肝炎病毒感染,肝功能正常的孕妇及新生儿（对照组）的临床资料、血清学检查结果、胎盘病理检查结果和胎儿预后进行分析,并对研究组中76例婴儿在出生后0、1、6月龄时分别注射酵母菌重组乙型肝炎疫苗10μg,24月龄时检测婴儿HBV表面抗体（HBsAb),以评价母婴HBV阻断效果。结果：（1）研究组胎儿窘迫的发生率为38．3％,对照组为16．5％,两组比较差异有显著性（P＜0．05）。（2）HBV感染胎盘可导致绒毛膜血管病。（3胎儿窘迫者,24月龄时母婴阻断率为78．6％,无胎儿窘迫者母婴HBV阻断率为91．7％,两 者比较,差异有显著性（P＜0．05）。结论：妊娠合并HBV感染,可引起胎盘绒毛膜血管病,致使胎盘功能下降,临床表现为胎儿窘迫、进而导致HBV母婴阻断失败。     

乙型肝炎疫苗和乙肝免疫球蛋白阻断乙肝病毒母婴传播的效果

目的:调查实际应用中免疫预防阻断乙型肝炎病毒(HBV)母婴传播的效果,观察孕期注射乙肝免疫球蛋白(HBIG)能否减少HBV母婴感染。方法:对2006年1月至2010年12月在镇江市妇幼保健院分娩的224例乙肝表面抗原(HBsAg)阳性母亲以及250例儿童,结合住院病历,进行回顾性调查,记录母亲孕期HBIG使用情况、子女出生后HBIG和乙型肝炎疫苗接种资料,并采血检测HBV血清标志物及谷丙转氨酶(ALT)。其中69例儿童出生后免疫预防前采外周血检测HBV血清标志物。结果:250例HBsAg阳性孕妇的子女随访时年龄(3.3±1.6)岁,出生时检测HBV标志物的69例中,4例HB-sAg阳性,其中2例随访时HBsAg仍阳性,乙型肝炎e抗原(HBeAg)也阳性,说明慢性感染,另外2例HBsAg转阴;1例出生时HBsAg阴性,但随访时转为阳性。另1例出生时未检测,随访时HBsAg阳性。因此共4例(1.6%)慢性感染HBV,其母亲均为HBeAg阳性。4例感染儿童中,2例出生时未注射HBIG,且未正规接种疫苗。随访的224例母亲中,215例明确孕期使用HBIG的情况;76例子女的母亲孕期注射了HBIG,1例(1.3%)HBsAg阳性,142例子女的139例母亲孕期未使用HBIG,3例(2.1%)HBsAg阳性(P>0.05)。结论:HBsAg阳性孕妇的子女经正规免疫预防后,HBV母婴阻断效果良好,部分预防失败是由于未实施正规预防。新生儿出生时HBV血清标志物不能作为诊断是否感染HBV的指标。孕晚期使用HBIG对阻断母婴感染无效。     

Hepatitis B – Vertical transmission and the prevention of mother-to-child transmission

Hepatitis B virus (HBV) infection is the commonest cause of chronic hepatitis, with an estimated global prevalence of 3.5%, and which leads to significant morbidity and mortality. Mother-to-child transmission (MTCT) during pregnancy is the leading form of transmission in endemic populations, and its interruption is thus crucial as the initial step in the elimination of HBV infection, notwithstanding the availability of potent antiviral medications. The risk of MTCT is dramatically reduced by timely neonatal HBV vaccination and the administration of hepatitis B immunoglobulin after birth in high-risk infants. Maternal HBV DNA quantification during pregnancy allows the assessment of the risk of newborn immunoprophylaxis failure (IF). Maternal antiviral treatment in highly viremic women can reduce the risk of IF. However, the optimal HBV DNA cutoff level for the initiation of antiviral treatment remains to be determined.