作者投稿
专家审稿
编辑办公
邮件订阅
RSS
-
摘要: 炎症性肠病大多于中青年发病, 会面临生育问题, 故加强妊娠前咨询、优化妊娠期管理可改善不良妊娠结局, 提高患者生命质量。本共识基于循证医学依据和Delphi方法, 在妊娠前指导和管理、妊娠期管理、分娩方式、哺乳期管理和婴儿疫苗接种共5个方面达成初步共识, 为临床工作提供指导。
-
中枢神经系统感染性疾病是临床重要的急危重症，在世界范围内具有较高的发病率和病死率[1]。早期识别致病病原体并给予针对性治疗，是改善患者预后的关键[2]。尽管如此，采用传统的病原学检测技术进行中枢神经系统感染性疾病诊断，仍存在超过半数的感染无法明确病原体[3]。宏基因组高通量测序(metage-nomic next-generation sequencing，mNGS) 技术可非靶向检测临床标本中存在的细菌、真菌、病毒和寄生虫等病原体核酸，具有广谱和灵敏度高的特点，其临床应用越来越广泛。目前，国内外相关研究也肯定了mNGS技术在中枢神经系统感染性疾病中的诊断价值[2, 4-7]。
2017年，中国医学科学院北京协和医院检验科团队开始探索建立mNGS检测技术流程，并于2022年正式投入临床应用。不同于第三方实验室，该检测平台的报告解读基于技术解读和临床解读两个层面，由从事生物信息学、临床感染、临床微生物学等专业人员合作完成。本研究基于该检测平台，对临床诊断为中枢神经系统感染性疾病患者的脑脊液mNGS检测结果进行回顾性分析，评价其在中枢神经系统感染性疾病诊断中的价值。
1. 资料与方法
1.1 临床资料
本研究为回顾性诊断性试验，研究对象为2022年4—12月于中国医学科学院北京协和医院就诊的患者。纳入标准：(1)患者最终临床诊断为中枢神经系统感染性疾病，参考《北京脑炎协作组脑炎诊断标准》[8]；(2)行脑脊液mNGS检测。排除标准：脑脊液细胞学证实为中枢神经系统恶性肿瘤或已确诊为自身免疫性脑炎的患者。
本研究已通过中国医学科学院北京协和医院伦理审查委员会审批(审批号：I-23ZM0049)，并豁免患者知情同意。
1.2 研究方法
登录医院信息系统，查阅并收集平台投入临床使用以来患者脑脊液mNGS检测报告结果，同时收集患者的相关临床信息、脑脊液常规、生化及病原学检查等资料。
脑脊液mNGS检测由中国医学科学院北京协和医院感染性疾病宏基因组检测平台开展。具体方法：采集患者1~2 mL脑脊液标本送检，同步进行DNA和RNA核酸提取，随后进行文库构建，并在Illumina平台进行测序，通过数据分析(广州微远基因生物公司提供平台及协和自建分析流程)，获得微生物检出及比对结果。
mNGS的结果解读流程分为技术解读和临床解读两个层面[9]，解读人员由多名具有丰富mNGS报告解读经验的人员构成，包括1名具有生物信息学教育背景的人员、1名具有临床检验诊断学及生物信息学专业知识的人员、1名具有微生物学及感染病学专业知识的人员。
以患者的临床诊断作为金标准，相关定义如下：(1)真阳性：mNGS检出病原体，且与患者的临床诊断符合；(2)假阴性：mNGS未检出病原体，但患者的临床诊断为中枢神经系统感染。
1.3 样本量估算
根据既往研究数据[2-3]，采用样本量计算公式：$ n=p(1-p)\left(\frac{z_{1-\alpha / 2}+z_{1-\beta}}{p-p_0}\right)^2$，取双侧检验，在α=0.05，β=0.1的条件下，计算本研究所需最小样本量为19例。
1.4 统计学处理
采用SPSS 26.0统计软件对数据进行分析，符合正态分布的计量资料以均数±标准差表示，偏态分布的计量资料以中位数(四分位数)表示，计数资料采用频数(百分数)表示。
2. 结果
2.1 患者临床资料
共入选39例符合纳入和排除标准的中枢神经系统感染性疾病患者，其中男性22例(56.4%)，女性17例(43.6%)，平均年龄(50.5±15.9)岁。主要临床表现为发热、头痛、意识障碍、癫痫发作、肢体麻木/无力、大小便障碍等(表 1)。急性病程22例(56.4%)，亚急性/慢性病程17例(43.6%)。患者入院后均完善腰椎穿刺检查，并送检脑脊液常规和生化检查，脑脊液白细胞计数为148(62，221)×106 /L，蛋白为1.46(0.89，2.45)g/L，葡萄糖为3.2(2.0，4.6)mmol/L，氯化物为(117.9±9.1)mmol/L。
表 1 39例中枢神经系统感染者的临床表现[n(%)]临床表现 数值 发热 27(69.2) 头痛 19(48.7) 呕吐 4(10.3) 意识障碍 17(43.6) 癫痫发作 5(12.8) 肢体麻木/无力 4(10.3) 精神行为异常 2(5.1) 认知功能下降 2(5.1) 大小便障碍 2(5.1) 视物模糊 1(2.6) 听力下降 1(2.6) 语言障碍 1(2.6) 吞咽障碍 1(2.6) 行走不稳 1(2.6) 颅内占位 2(5.1) 皮疹 5(12.8) 2.2 脑脊液mNGS检测结果与临床验证
在39例患者中，10例(25.6%)脑脊液mNGS报告结果为阴性；29例(74.4%)检出疑似致病病原体特异性序列，其中11例(37.9%)检出细菌，13例(44.8%)检出病毒，3例(10.3%)检出真菌，1例(3.5%)检出细菌及病毒，1例(3.5%)检出真菌及病毒。检出细菌以结核分枝杆菌最为常见(6例)，其次为金黄色葡萄球菌(2例)、肺炎克雷伯菌(1例)、屎肠球菌及肺炎克雷伯菌混合感染(1例)、链球菌属及表皮葡萄球菌(各1例)。检出病毒以水痘-带状疱疹病毒最为常见(9例)，其次为EB病毒(3例，其中1例同时检出新型隐球菌及EB病毒)、巨细胞病毒(2例，其中1例同时检出链球菌属及巨细胞病毒)及肠道病毒71型(1例)。检出真菌以新型隐球菌最为常见(2例)，其次为白色念珠菌(1例)及烟曲霉(1例)。
29例阳性病例脑脊液mNGS检测结果均与临床诊断相符，真阳性率为74.4%。阳性病例脑脊液mNGS病原体检测结果与临床验证情况详见表 2。在检出结核分枝杆菌的6例患者中，除1例患者于送检当日死亡外，其余5例患者临床诊断均为结核性脑膜炎/脑膜脑炎，并接受抗结核治疗。在此6例患者中，4例送检脑脊液X-pert® MTB/XDR检测，仅1例结果为阳性；2例送检脑脊液结核分枝杆菌核酸聚合酶链式反应(polymerase chain reaction，PCR)检测，结果均为阴性。在mNGS检出细菌阳性(含细菌及病毒混合检出1例)的其他患者中，除1例患者(检出金黄色葡萄球菌阳性)入院后死亡未留取病原学标本外，其余5例检测结果均与血培养/脑脊液/硬膜外脓肿脓液培养结果一致。在检出病毒的患者中，除2例细菌及真菌混合感染外，其余13例临床诊断均为病毒性中枢神经系统感染，并接受抗病毒治疗，2例脑脊液病毒核酸PCR检测阳性。在mNGS检出真菌(含真菌及病毒混合检出1例)的患者中，仅1例脑脊液培养为阳性，2例检出新型隐球菌的病例其脑脊液隐球菌抗原均为阳性，1例检出烟曲霉的病例其血曲霉半乳甘露聚糖(galactomannan，GM)试验为阳性。
表 2 29例阳性病例脑脊液mNGS病原体检测结果与临床验证情况mNGS检测结果 临床验证方法 细菌感染(12例) 结核分枝杆菌(6例) 临床诊断结核性脑膜炎/脑膜脑炎并接受抗结核治疗(5例) 涂片阳性肺结核(1例) 脑脊液X-pert® MTB/XDR检测阳性(1例) 金黄色葡萄球菌(2例) 血培养阳性(1例) 脑脊液白细胞明显升高且以多个核细胞为主(2例) 肺炎克雷伯菌(1例) 血培养阳性(1例) 屎肠球菌及肺炎克雷伯菌混合感染(1例) 硬膜外脓肿脓液培养阳性(1例) 链球菌属(1例) 脑脊液培养阳性(1例) 表皮葡萄球菌(1例) 脑脊液培养阳性(1例) 病毒感染(13例，除外2例混合感染) 水痘‐带状疱疹病毒(9例) 临床诊断病毒性脑膜炎/脑膜脑炎/脑脊髓炎并接受抗病毒治疗(9例) 疱疹(5例) EB病毒(2例) 脑脊液EB病毒核酸PCR检测阳性(1例) 临床诊断病毒性脑膜炎/脑炎并接受抗病毒治疗(2例) 巨细胞病毒(1例) 脑脊液巨细胞病毒核酸PCR检测阳性(1例) 临床诊断病毒性脑膜炎/脑炎并接受抗病毒治疗(1例) 肠道病毒71型(1例) 临床诊断病毒性脑膜炎并接受抗病毒治疗(1例) 真菌感染(4例) 新型隐球菌(2例) 脑脊液隐球菌抗原阳性(2例) 脑脊液培养阳性(1例) 烟曲霉(1例) 血曲霉半乳甘露聚糖试验阳性(1例) 白色念珠菌(1例) 临床诊断念珠菌性中枢神经系统感染(1例) mNGS：宏基因组高通量测序；PCR：聚合酶链式反应 10例(25.6%)患者的mNGS检测结果为假阴性，根据其临床表现、脑脊液常规及生化结果等判断，临床诊断为中枢神经系统病毒感染4例，考虑细菌感染4例，无明确病原学指向2例。此10例患者的脑脊液临床常规病原学检查无阳性结果回报。
38例患者进行了脑脊液临床常规病原学检查(包括脑脊液涂片、培养、病原体抗原及PCR核酸检测)。5例(13.2%)脑脊液/硬膜外脓肿脓液培养阳性，其中细菌4例，真菌1例。1例脑脊液X-pert® MTB/XDR检测阳性，2例脑脊液病毒核酸PCR检测阳性，2例脑脊液隐球菌抗原检测阳性。整体脑脊液临床常规病原学检查的阳性率为23.7%(9/38)。
39例中枢神经系统感染患者中，16例临床诊断为细菌感染(包括7例结核性脑膜炎/脑膜脑炎、5例化脓性脑膜炎、3例脑脓肿及1例硬膜外脓肿)，17例临床诊断为病毒感染(包括8例脑膜炎、4例脑炎、3例脑膜脑炎、1例脑脊髓炎及1例脑脊髓膜炎)，4例临床诊断为真菌感染(包括2例隐球菌性脑膜炎、1例烟曲霉及1例念珠菌性中枢神经系统感染)，2例临床无明确病原学指向。mNGS病原体检测结果与临床诊断比较详见表 3。对于结核性脑膜炎/脑膜脑炎，mNGS诊断的灵敏度、特异度分别为85.7%、100%；对于其他中枢神经系统细菌感染，mNGS诊断的灵敏度、特异度分别为66.7%、100%；对于中枢神经系统病毒感染，mNGS诊断的灵敏度、特异度分别为76.5%、86.4%；对于中枢神经系统真菌感染，mNGS诊断的灵敏度、特异度均为100%。
表 3 mNGS病原体检测结果与临床诊断比较[n(%)]mNGS检测结果 临床诊断 细菌(n=9) 结核(n=7) 病毒(n=17) 真菌(n=4) 检出对应致病病原体(n=29) 6(66.7) 6(85.7) 13(76.5) 4(100) 未检出对应致病病原体(n=10)* 3(33.3) 1(14.3) 4(23.5) 0(0) mNGS: 同表 2；*包含2例临床无明确病原学指向的中枢神经系统感染病例 3. 讨论
本研究通过回顾性分析发现，39例临床诊断为中枢性神经系统感染性疾病患者中，29例通过mNGS检出疑似致病病原体，且均与临床诊断一致，真阳性率为74.4%，显著高于常规病原学检查结果(74.4%比23.7%)。
中枢神经系统感染性疾病作为临床急危重症，对致病病原体的早期识别和治疗是改善患者预后的关键[2]。脑脊液涂片及培养作为传统的病原学检测方法，不仅阳性率低，且培养耗时较长，不利于早期诊断。尽管脑脊液病原学抗原检测及基于PCR的核酸检测在临床逐渐推广，但其联合涂片及培养检测的阳性率未超过50%[2-3, 5]。为提高检测的阳性率，缩短检测时间，有研究引入质谱技术，无需进行培养即可直接检出脑脊液中的病原体[10]，但目前该技术在国内外应用的报道较少，且脑脊液中需含有较高的菌量方可检出[11]。mNGS技术相较于传统检测方法，灵敏度更高且耗时更短，有助于临床疑难及急危重感染性疾病病原体的快速识别和诊断。
目前，国内外相关研究对mNGS技术在中枢神经系统感染性疾病诊断中的价值进行了探讨。国外一项纳入213例中枢神经系统感染性疾病患者的多中心、前瞻性研究显示，mNGS技术在中枢神经系统感染性疾病中的病原体阳性检出率为57%，在检测病毒、细菌及结核分枝杆菌感染方面优于传统检测手段[5]。国内研究显示，mNGS技术对中枢神经系统感染性疾病的病原体阳性检出率为41%~47%[7, 12-13]。尽管mNGS技术在结核分枝杆菌的检出方面存在一定局限性(核酸提取难度大，导致检出序列少或出现假阴性)[14]，但本研究依然显示出脑脊液mNGS检测在结核性脑膜炎/脑膜脑炎诊断中的优势，在7例临床表现及脑脊液检测诊断为结核性脑膜炎/脑膜脑炎的病例中，6例mNGS检出结核分枝杆菌，灵敏度为85.7%。而在此7例患者中，仅1例(14.3%) 痰抗酸染色为阳性，1例(14.3%)结核分枝杆菌PCR检测为阳性，mNGS检测的阳性率明显高于临床常规检测手段。且脑脊液mNGS检出结核分枝杆菌亦具有极好的特异性，这与国外文献报道一致[5, 15]。
mNGS检出的29例阳性病例均与临床诊断相符，并可通过病原学检查(脑脊液涂片、培养、病原体抗原及PCR检测)验证或接受相应的抗微生物治疗。但在mNGS检出病毒的病例中，2例确诊为中枢神经系统细菌/真菌感染的病例同时检出了超过10条序列的病毒，且均为条件致病病毒(EB病毒及巨细胞病毒各1例)，考虑可能为机体的潜伏感染。
本研究中，mNGS技术检出病原体的真阳性率为74.4%，高于国内外文献报道，此结果与本实验室对于报告解读流程的改进有关。mNGS技术的检测流程复杂，检测结果易受多方面因素的影响，实验室及试剂中的背景微生物、腰椎穿刺采样过程中皮肤定植菌的污染、采样及送检过程中环境微生物的污染等均对检测报告的解读存在干扰。目前，国内mNGS检测分为院内检测和第三方实验室检测两种方式。自2017年起，中国医学科学院院北京协和医院检验科团队从临床需求出发，先后建立了mNGS的湿实验流程、生物信息分析流程、背景核酸数据模型，形成了相对规范的mNGS检测流程[16-18]。在临床应用前，本团队结合已发表的专家共识[14, 19]，与急诊科、重症医学科、感染内科、神经科等多个科室的医师团队共同撰写报告解读流程文件[9, 20]。在报告解读过程中，通过背景核酸数据模型过滤试剂、采样、环境中的背景微生物，同时结合患者的临床病史、脑脊液常规检测结果、病原学检测结果、影像学检查结果等综合判断检出结果与临床的一致性，最大可能避免假阳性报告的签发。同时，对于临床疑似中枢神经系统感染的患者标本，在首次检测结果未检出明确病原体的情况下，检验医师在查阅临床病例资料后指导调整湿实验流程，如提高破壁强度以提升真菌、结核分枝杆菌的核酸提取效率[21-22]，增加去宿主流程以降低人源基因的比例，提升检测的真阳性率[23-24]。对于疑难病例，实验室则通过反复临床沟通、多学科会诊等策略与临床医师合作，尽可能解决临床问题。
本研究局限性：共纳入39例中枢神经系统感染性疾病病例，样本量相对较小，可能影响结果的外推性。mNGS技术作为新兴的检测技术，相较于传统检查手段，目前费用昂贵，同时对检测人员和解读人员的要求也更高，在一定程度上限制了其临床应用。随着技术的不断进步，通过降低成本费用、简化检测流程、缩短周转时间，相信mNGS技术可得到更广泛的应用。
综上，在中枢神经系统感染性疾病病原体检测方面，脑脊液mNGS检测相较于现有临床常规病原学检测手段具有更高的真阳性率，能够较为高效、快速、准确地获得致病病原体的信息，对于中枢神经系统感染性疾病的早期诊断及治疗、改善患者临床预后具有重要价值。
利益冲突 无 -
表 1 炎症性肠病患者常用药物在妊娠期和哺乳期的用药风险
药物 妊娠期用药风险 哺乳期用药风险 美沙拉秦 低风险 低风险 柳氮磺吡啶 低风险 慎用 糖皮质激素 低风险 低风险 硫唑嘌呤 低风险 慎用(有争议) 抗肿瘤坏死因子α单克隆抗体 低风险 低风险 维多珠单克隆抗体 未知 未知 甲氨蝶呤 禁用 禁用 沙利度胺 禁用 禁用 环孢素 慎用 禁用 
下载: 导出CSV
-
[1] Martin L, Peche W, Peterson K, et al.Population Based Paternity Rate and Partner Birth Outcomes Among Utah Men With Inflammatory Bowel Disease[J]. Am J Gastroenterol, 2017, 112:1722-1727. DOI: 10.1038/ajg.2017.279
[2] Tavernier N, Fumery M, Peyrin-Biroulet L, et al.Systematic review:fertility in non-surgically treated inflammatory bowel disease[J]. Aliment Pharmacol Ther, 2013, 38:847-853. DOI: 10.1111/apt.12478
[3] Mayberry JF, Weterman IT. European survey of fertility and pregnancy in women with Crohn's disease:a case control study by European collaborative group[J]. Gut, 1986, 27:821-825. DOI: 10.1136/gut.27.7.821
[4] Marri SR, Ahn C, Buchman AL. Voluntary childlessness is increased in women with inflammatory bowel disease[J]. Inflamm Bowel Dis, 2007, 13:591-599. DOI: 10.1002/ibd.20082
[5] Ording Olsen K, Juul S, Berndtsson I, et al. Ulcerative colitis:female fecundity before diagnosis, during disease, and after surgery compared with a population sample[J]. Gastroenterology, 2002, 122:15-19. DOI: 10.1053/gast.2002.30345
[6] Waljee A. Waljee J, Morris AM, et al. Threefold increased risk of infertility:a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis[J]. Gut, 2006, 55:1575-1580. DOI: 10.1136/gut.2005.090316
[7] Rajaratnam SG, Eglinton TW, Hider P, et al.Impact of ileal pouch-anal anastomosis on female fertility:meta-analysis and systematic review[J]. Int J Colorectal Dis, 2011, 26:1365-1374. DOI: 10.1007/s00384-011-1274-9
[8] Ananthakrishnan AN, Martin C, Kane S, et al. Paternal Disease Activity Is Associated With Difficulty in Conception Among Men With Inflammatory Bowel Diseases[J]. Clin Gastroenterol Hepatol, 2019, 17:203-204. DOI: 10.1016/j.cgh.2018.04.001
[9] Orholm M, Munkholm P, Langholz E, et al. Familial occurrence of inflammatory bowel disease[J]. N Engl J Med, 1991, 324:84-88. DOI: 10.1056/NEJM199101103240203
[10] Peeters M, Nevens H, Baert F, et al. Familial aggregation in Crohn's disease:increased age-adjusted risk and concordance in clinical characteristics[J]. Gastroenterology, 1996, 111:597-603. DOI: 10.1053/gast.1996.v111.pm8780562
[11] Jolving LR, Nielsen J, Beck-Nielsen SS, et al. The Association Between Maternal Chronic Inflammatory Bowel Disease and Long-term Health Outcomes in Children-A Nationwide Cohort Study[J]. Inflamm Bowel Dis, 2017, 23:1440-1446. DOI: 10.1097/MIB.0000000000001146
[12] Orholm M, Fonager K, Sorensen HT. Risk of ulcerative colitis and Crohn's disease among offspring of patients with chronic inflammatory bowel disease[J]. Am J Gastroenterol, 1999, 94:3236-3238. DOI: 10.1111/j.1572-0241.1999.01526.x
[13] Bennett RA, Rubin PH, Present DH. Frequency of inflammatory bowel disease in offspring of couples both presenting with inflammatory bowel disease[J]. Gastroenterology, 1991, 100:1638-1643. DOI: 10.1016/0016-5085(91)90663-6
[14] Laharie D, Debeugny S, Peeters M, et al.Inflammatory bowel disease in spouses and their offspring[J]. Gastroenterology, 2001, 120:816-819. DOI: 10.1053/gast.2001.22574
[15] Julsgaard M, Norgaard M, Hvas CL, et al.Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis[J]. Inflamm Bowel Dis, 2011, 17:1573-1580. DOI: 10.1002/ibd.21522
[16] Nielsen MJ, Norgaard M, Holland-Fisher P, et al.Self-reported antenatal adherence to medical treatment among pregnant women with Crohn's disease[J]. Aliment Pharmacol Ther, 2010, 32:49-58. DOI: 10.1111/j.1365-2036.2010.04318.x
[17] de Lima A, Zelinkova Z, Mulders AG, et al. Preconception Care Reduces Relapse of Inflammatory Bowel Disease During Pregnancy[J]. Clin Gastroenterol Hepatol, 2016, 14:1285-1292.e1. DOI: 10.1016/j.cgh.2016.03.018
[18] Mountifield R, Andrews JM, Bampton P.It is worth the effort:Patient knowledge of reproductive aspects of inflammatory bowel disease improves dramatically after a single group education session[J]. J Crohns Colitis, 2014, 8:796-801. DOI: 10.1016/j.crohns.2013.12.019
[19] Reddy D, Murphy SJ, Kane SV, et al.Relapses of inflammatory bowel disease during pregnancy:in-hospital management and birth outcomes[J]. Am J Gastroenterol, 2008, 103:1203-1209. DOI: 10.1111/j.1572-0241.2007.01756.x
[20] Pedersen N, Bortoli A, Duricova D, et al. The course of inflammatory bowel disease during pregnancy and postpartum:a prospective European ECCO-EpiCom Study of 209 pregnant women[J]. Aliment Pharmacol Ther, 2013, 38:501-512. DOI: 10.1111/apt.12412
[21] Miller JP.Inflammatory bowel disease in pregnancy:a review[J]. J R Soc Med, 1986, 79:221-225. DOI: 10.1177/014107688607900410
[22] Bengtson MB, Solberg IC, Aamodt G, et al. Relationships between inflammatory bowel disease and perinatal factors:both maternal and paternal disease are related to preterm birth of offspring[J]. Inflamm Bowel Dis, 2010, 16:847-855. DOI: 10.1002/ibd.21120
[23] Mahadevan U, Sandborn WJ, Li DK, et al. Pregnancy outcomes in women with inflammatory bowel disease:a large community-based study from Northern California[J]. Gastroenterology, 2007, 133:1106-1112. DOI: 10.1053/j.gastro.2007.07.019
[24] Naganuma M, Kunisaki R, Yoshimura N, et al. Conception and pregnancy outcome in women with inflammatory bowel disease:A multicentre study from Japan[J]. J Crohns Colitis, 2011, 5:317-323. DOI: 10.1016/j.crohns.2011.02.003
[25] Stephansson O, Larsson H, Pedersen L, et al. Congenital abnormalities and other birth outcomes in children born to women with ulcerative colitis in Denmark and Sweden[J]. Inflamm Bowel Dis, 2011, 17:795-801. DOI: 10.1002/ibd.21369
[26] Cornish J, Tan E, Teare J, et al. A meta-analysis on the influence of inflammatory bowel disease on pregnancy[J]. Gut, 2007, 56:830-837. DOI: 10.1136/gut.2006.108324
[27] Lin HC, Chiu CC, Chen SF, et al. Ulcerative colitis and pregnancy outcomes in an Asian population[J]. Am J Gastroenterol, 2010, 105:387-394. DOI: 10.1038/ajg.2009.562
[28] Bortoli A, Pedersen N, Duricova D, et al. Pregnancy outcome in inflammatory bowel disease:prospective European case-control ECCO-EpiCom study, 2003-2006[J]. Aliment Pharmacol Ther, 2011, 34:724-734. DOI: 10.1111/j.1365-2036.2011.04794.x
[29] Ito A, Iizuka B, Omori T, et al.Relationship between the Clinical Course of Ulcerative Colitis during Pregnancy and the Outcomes of Pregnancy:A Retrospective Evaluation[J]. Intern Med, 2018, 57:159-164. DOI: 10.2169/internalmedicine.8550-16
[30] Ujihara M, Ando T, Ishiguro K, et al. Importance of appropriate pharmaceutical management in pregnant women with ulcerative colitis[J]. BMC Res Notes, 2013, 6:210. DOI: 10.1186/1756-0500-6-210
[31] Bressler B, Marshall JK, Bernstein CN, et al. Clinical practice guidelines for the medical management of nonhospita-lized ulcerative colitis:the Toronto consensus[J]. Gastroenterology, 2015, 148:1035-1058.e3. DOI: 10.1053/j.gastro.2015.03.001
[32] Neurath MF, Travis SP. Mucosal healing in inflammatory bowel diseases:a systematic review[J]. Gut, 2012, 61:1619-1635. DOI: 10.1136/gutjnl-2012-302830
[33] Hanan IM. Inflammatory bowel disease in the pregnant woman[J]. Compr Ther, 1998, 24:409-414.
[34] Kelley KE, Hernandez-Diaz S, Chaplin EL, et al. Identification of phthalates in medications and dietary supplement formulations in the United States and Canada[J]. Environ Health Perspect, 2012, 120:379-384. DOI: 10.1289/ehp.1103998
[35] Hernandez-Diaz S, Su YC, Mitchell AA, et al.Medications as a potential source of exposure to phthalates among women of childbearing age[J]. Reprod Toxicol, 2013, 37:1-5. DOI: 10.1016/j.reprotox.2013.01.001
[36] Dalrymple JM, Stamp LK, O'Donnell JL, et al. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis[J]. Arthritis Rheum, 2008, 58:3299-3308. DOI: 10.1002/art.24034
[37] Dara P, Slater LM, Armentrout SA.Successful pregnancy during chemotherapy for acute leukemia[J]. Cancer, 1981, 47:845-846. DOI: 10.1002/1097-0142(19810301)47:5<845::AID-CNCR2820470504>3.0.CO;2-4
[38] Kozlowski RD, Steinbrunner JV, MacKenzie AH, et al.Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease[J]. Am J Med, 1990, 88:589-592. DOI: 10.1016/0002-9343(90)90522-F
[39] Martinez Lopez JA, Loza E, Carmona L. Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding)[J]. Clin Exp Rheumatol, 2009, 27:678-684. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=b3b901f6691248c0e24c99182e1f4c78
[40] Hernandez-Diaz S, Werler MM, Walker AM, et al.Folic acid antagonists during pregnancy and the risk of birth defects[J]. N Engl J Med, 2000, 343:1608-1614. DOI: 10.1056/NEJM200011303432204
[41] Smithells RW, Newman CG. Recognition of thalidomide defects[J]. J Med Genet, 1992, 29:716-723. DOI: 10.1136/jmg.29.10.716
[42] Peng X, Zhi M, Wei M, et al. Thalidomide results in diminished ovarian reserve in reproductive age female IBD patients[J]. Medicine (Baltimore), 2017, 96:e6540. DOI: 10.1097/MD.0000000000006540
[43] O'Morain C, Smethurst P, Dore CJ, et al. Reversible male infertility due to sulphasalazine:studies in man and rat[J]. Gut, 1984, 25:1078-1784. DOI: 10.1136/gut.25.10.1078
[44] Mahadevan U, Terdiman JP, Aron J, et al. Infliximab and semen quality in men with inflammatory bowel disease[J]. Inflamm Bowel Dis, 2005, 11:395-399. DOI: 10.1097/01.MIB.0000164023.10848.c4
[45] Villiger PM, Caliezi G, Cottin V, et al. Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis[J]. Ann Rheum Dis, 2010, 69:1842-1844. DOI: 10.1136/ard.2009.127423
[46] Teruel C, Lopez-San Roman A, Bermejo F, et al. Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines[J]. Am J Gastroenterol, 2010, 105:2003-2008. DOI: 10.1038/ajg.2010.138
[47] Dejaco C, Mittermaier C, Reinisch W, et al. Azathioprine treatment and male fertility in inflammatory bowel disease[J]. Gastroenterology, 2001, 121:1048-1053. DOI: 10.1053/gast.2001.28692
[48] Norgard B, Czeizel AE, Rockenbauer M, et al. Population-based case control study of the safety of sulfasalazine use during pregnancy[J]. Aliment Pharmacol Ther, 2001, 15:483-486. DOI: 10.1046/j.1365-2036.2001.00962.x
[49] Rahimi R, Nikfar S, Rezaie A, et al. Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs:a meta-analysis[J]. Reprod Toxicol, 2008, 25:271-275. DOI: 10.1016/j.reprotox.2007.11.010
[50] Norgard B, Fonager K, Pedersen L, et al.Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy:a Danish cohort study[J]. Gut, 2003, 52:243-237. DOI: 10.1136/gut.52.2.243
[51] Akbari M, Shah S, Velayos FS, et al. Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease[J]. Inflamm Bowel Dis, 2013, 19:15-22. DOI: 10.1002/ibd.22948
[52] Coelho J, Beaugerie L, Colombel JF, et al. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines:cohort from the CESAME Study[J]. Gut, 2011, 60:198-203. DOI: 10.1136/gut.2010.222893
[53] Casanova MJ, Chaparro M, Domenech E, et al. Safety of thiopurines and anti-TNF-alpha drugs during pregnancy in patients with inflammatory bowel disease[J]. Am J Gastroenterol, 2013, 108:433-440. DOI: 10.1038/ajg.2012.430
[54] Langagergaard V, Pedersen L, Gislum M, et al. Birth outcome in women treated with azathioprine or mercaptopurine during pregnancy:A Danish nationwide cohort study[J]. Aliment Pharmacol Ther, 2007, 25:73-81.
[55] Kanis SL, de Lima-Karagiannis A, de Boer NKH, et al. Use of Thiopurines During Conception and Pregnancy Is Not Associated With Adverse Pregnancy Outcomes or Health of Infants at One Year in a Prospective Study[J]. Clin Gastroenterol Hepatol, 2017, 15:1232-1241.e1. DOI: 10.1016/j.cgh.2017.02.041
[56] Kane SV, Acquah LA. Placental transport of immunoglobulins:a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy[J]. Am J Gastroenterol, 2009, 104:228-233. DOI: 10.1038/ajg.2008.71
[57] Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease[J]. Clin Gastroenterol Hepatol, 2013, 11:286-292, e24. DOI: 10.1016/j.cgh.2012.11.011
[58] Cheent K, Nolan J, Shariq S, et al. Case Report:Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease[J]. J Crohns Colitis, 2010, 4:603-605. DOI: 10.1016/j.crohns.2010.05.001
[59] Mahadevan U, Martin CF, Sandler RS, et al. PIANO:a 1000 patient prospective registry of pregnancy outcomes in women with ibd exposed to immunomodulators and biologic therapy[J]. Gastroenterology, 2012, 142:S149.
[60] Julsgaard M, Kjeldsen J, Baumgart DC.Vedolizumab safety in pregnancy and newborn outcomes[J]. Gut, 2017, 66:1866-1867. DOI: 10.1136/gutjnl-2016-313444
[61] Mahadevan U, Vermeire S, Lasch K, et al. Vedolizumab exposure in pregnancy:outcomes from clinical studies in inflammatory bowel disease[J]. Aliment Pharmacol Ther, 2017, 45:941-950. DOI: 10.1111/apt.13960
[62] Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids:prospective cohort study and meta-analysis of epidemiological studies[J]. Teratology, 2000, 62:385-392. DOI: 10.1002/1096-9926(200012)62:6<385::AID-TERA5>3.0.CO;2-Z
[63] Hviid A, Molgaard-Nielsen D.Corticosteroid use during pregnancy and risk of orofacial clefts[J]. Cmaj, 2011, 183:796-804. DOI: 10.1503/cmaj.101063
[64] Martel MJ, Rey E, Beauchesne MF, et al. Use of inhaled corticosteroids during pregnancy and risk of pregnancy induced hypertension:nested case-control study[J]. BMJ, 2005, 330:230. DOI: 10.1136/bmj.38313.624352.8F
[65] Bar Oz B, Hackman R, Einarson T, et al.Pregnancy outcome after cyclosporine therapy during pregnancy:a meta-analysis[J]. Transplantation, 2001, 71:1051-1055. DOI: 10.1097/00007890-200104270-00006
[66] Branche J, Cortot A, Bourreille A, et al. Cyclosporine treatment of steroid-refractory ulcerative colitis during pregnancy[J]. Inflamm Bowel Dis, 2009, 15:1044-1048. DOI: 10.1002/ibd.20858
[67] Piper JM, Mitchel EF, Ray WA.Prenatal use of metronidazole and birth defects:no association[J]. Obstet Gynecol, 1993, 82:348-352.
[68] Koss CA, Baras DC, Lane SD, et al. Investigation of metronidazole use during pregnancy and adverse birth outcomes[J]. Antimicrob Agents Chemother, 2012, 56:4800-4805. DOI: 10.1128/AAC.06477-11
[69] Linseman DA, Hampton LA, Branstetter DG. Quinolone-induced arthropathy in the neonatal mouse. Morphological analysis of articular lesions produced by pipemidic acid and ciprofloxacin[J]. Fundam Appl Toxicol, 1995, 28:59-64. DOI: 10.1006/faat.1995.1146
[70] Bernstein CN, Blanchard JF, Houston DS, et al. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease:a population-based cohort study[J]. Thromb Haemost, 2001, 85:430-434. DOI: 10.1055/s-0037-1615600
[71] Pomp ER, Lenselink AM, Rosendaal FR, et al. Pregnancy, the postpartum period and prothrombotic defects:risk of venous thrombosis in the MEGA study[J]. J Thromb Haemost, 2008, 6:632-637. DOI: 10.1111/j.1538-7836.2008.02921.x
[72] 中华医学会消化病学分会炎症性肠病学组.中国住院炎症性肠病患者静脉血栓栓塞症防治的专家共识意见[J].中华炎性肠病杂志, 2018, 2:75-82. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zhyxcbzz201802002 [73] Killeen S, Gunn J, Hartley J. Surgical management of complicated and medically refractory inflammatory bowel disease during pregnancy[J]. Colorectal Dis, 2017, 19:123-138. DOI: 10.1111/codi.13413
[74] Panes J, Bouzas R, Chaparro M, et al. Systematic review:the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn's disease[J]. Aliment Pharmacol Ther, 2011, 34:125-145. DOI: 10.1111/j.1365-2036.2011.04710.x
[75] Schreyer AG, Menzel C, Friedrich C, et al. Comparison of high-resolution ultrasound and MR-enterography in patients with inflammatory bowel disease[J]. World J Gastroenterol, 2011, 17:1018-1025. https://www.ncbi.nlm.nih.gov/pubmed/21448353
[76] Stern MD, Kopylov U, Ben-Horin S, et al. Magnetic resonance enterography in pregnant women with Crohn's disease:case series and literature review[J]. BMC Gastroenterol, 2014, 14:146. DOI: 10.1186/1471-230X-14-146
[77] Birchard KR, Brown MA, Hyslop WB, et al. MRI of acute abdominal and pelvic pain in pregnant patients[J]. AJR Am J Roentgenol, 2005, 184:452-458. DOI: 10.2214/ajr.184.2.01840452
[78] Tremblay E, Therasse E, Thomassin-Naggara I, et al. Quality initiatives:guidelines for use of medical imaging during pregnancy and lactation[J]. Radiographics, 2012, 32:897-911. DOI: 10.1148/rg.323115120
[79] Schulze H, Esters P, A Dignass.Review article:the management of Crohn's disease and ulcerative colitis during pregnancy and lactation[J]. Aliment Pharmacol Ther, 2014, 40:991-1008. DOI: 10.1111/apt.12949
[80] Nguyen GC, Seow CH, Maxwell C, et al. The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy[J]. Gastroenterology, 2016, 150:734-757.e1. DOI: 10.1053/j.gastro.2015.12.003
[81] van der Woude CJ, Ardizzone S, Bengtson MB, et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease[J]. J Crohns Colitis, 2015, 9:107-124. DOI: 10.1093/ecco-jcc/jju006
[82] Shergill AK, Ben-Menachem T, Chandrasekhara V, et al. Guidelines for endoscopy in pregnant and lactating women[J]. Gastrointest Endosc, 2012, 76:18-24. DOI: 10.1016/j.gie.2012.02.029
[83] Ludvigsson JF, Lebwohl B, Ekbom A, et al. Outcomes of Pregnancies for Women Undergoing Endoscopy While They Were Pregnant:A Nationwide Cohort Study[J]. Gastroenterology, 2017, 152:554-563.e9. DOI: 10.1053/j.gastro.2016.10.016
[84] De Lima A, Galjart B, Wisse PH, et al. Does lower gastrointestinal endoscopy during pregnancy pose a risk for mother and child?-a systematic review[J]. BMC Gastroenterol, 2015, 15:15. DOI: 10.1186/s12876-015-0244-z
[85] Abdul Sultan A, West J, Ban L, et al. Adverse Pregnancy Outcomes Among Women with Inflammatory Bowel Disease:A Population-Based Study from England[J]. Inflamm Bowel Dis, 2016, 22:1621-1630. DOI: 10.1097/MIB.0000000000000802
[86] Foulon A, Dupas JL, Sabbagh C, et al. Defining the Most Appropriate Delivery Mode in Women with Inflammatory Bowel Disease:A Systematic Review[J]. Inflamm Bowel Dis, 2017, 23:712-720. DOI: 10.1097/MIB.0000000000001112
[87] Ananthakrishnan AN, Cheng A, Cagan A, et al. Mode of childbirth and long-term outcomes in women with inflammatory bowel diseases[J]. Dig Dis Sci, 2015, 60:471-477. DOI: 10.1007/s10620-014-3353-6
[88] Grouin A, Brochard C, Siproudhis L, et al. Perianal Crohn's disease results in fewer pregnancies but is not exacerbated by vaginal delivery[J]. Dig Liver Dis, 2015, 47:1021-1026. DOI: 10.1016/j.dld.2015.08.001
[89] McConnell RA, Mahadevan U.Pregnancy and the Patient with Inflammatory Bowel Disease:Fertility, Treatment, Delivery, and Complications[J]. Gastroenterol Clin North Am, 2016, 45:285-301. DOI: 10.1016/j.gtc.2016.02.006
[90] Burke KE, Haviland MJ, Hacker MR, et al. Indications for Mode of Delivery in Pregnant Women with Inflammatory Bowel Disease[J]. Inflamm Bowel Dis, 2017, 23:721-726. DOI: 10.1097/MIB.0000000000001113
[91] Smink M, Lotgering FK, Albers L, et al. Effect of childbirth on the course of Crohn's disease; results from a retrospective cohort study in the Netherlands[J]. BMC Gastroenterol, 2011, 11:6. DOI: 10.1186/1471-230X-11-6
[92] Bernstein CN, Banerjee A, Targownik LE, et al. Cesarean Section Delivery Is Not a Risk Factor for Development of Inflammatory Bowel Disease:A Population-based Analysis[J]. Clin Gastroenterol Hepatol, 2016, 14:50-57. DOI: 10.1016/j.cgh.2015.08.005
[93] Mahadevan U, McConnell RA, Chambers CD. Drug Safety and Risk of Adverse Outcomes for Pregnant Patients With Inflammatory Bowel Disease[J]. Gastroenterology, 2017, 152:451-462.e2. DOI: 10.1053/j.gastro.2016.10.013
[94] Branski D, Kerem E, Gross-Kieselstein E, et al. Bloody diarrhea-a possible complication of sulfasalazine transferred through human breast milk[J]. J Pediatr Gastroenterol Nutr, 1986, 5:316-317. DOI: 10.1097/00005176-198605020-00028
[95] Van Assche G, Dignass A, Reinisch W, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease:Special situations[J]. J Crohns Colitis, 2010, 4:63-101. DOI: 10.1016/j.crohns.2009.09.009
[96] Ng SW, Mahadevan U. Management of inflammatory bowel disease in pregnancy[J]. Expert Rev Clin Immunol, 2013, 9:161-73; quiz 174. [97] Christensen LA, Dahlerup JF, Nielsen MJ, et al. Azathioprine treatment during lactation[J]. Aliment Pharmacol Ther, 2008, 28:1209-1213. DOI: 10.1111/j.1365-2036.2008.03843.x
[98] Sau A, Clarke S, Bass J, et al. Azathioprine and breastfeeding:is it safe?[J]. BJOG, 2007, 114:498-501. DOI: 10.1111/j.1471-0528.2006.01232.x
[99] Sammaritano LR, Bermas BL.Rheumatoid arthritis medications and lactation[J]. Curr Opin Rheumatol, 2014, 26:354-360. DOI: 10.1097/BOR.0000000000000055
[100] Moretti ME, Verjee Z, Ito S, et al. Breast-feeding during maternal use of azathioprine[J]. Ann Pharmacother, 2006, 40:2269-2272. DOI: 10.1345/aph.1H152
[101] Gotestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation[J]. Ann Rheum Dis, 2016, 75:795-810. DOI: 10.1136/annrheumdis-2015-208840
[102] Zelinkova Z, De Boer IP, Van Dijke MJ, et al. Azathioprine treatment during lactation[J]. Aliment Pharmacol Ther, 2009. 30: 90-91; author reply 91.
[103] Nielsen OH, Maxwell C, Hendel J. IBD medications during pregnancy and lactation[J]. Nat Rev Gastroenterol Hepatol, 2014, 11:116-127. DOI: 10.1038/nrgastro.2013.135
[104] Niebyl JR.Antibiotics and other anti-infective agents in pregnancy and lactation[J]. Am J Perinatol, 2003, 20:405-414. DOI: 10.1055/s-2003-45391
[105] WHO. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans: Vol. 50 Pharmaceutical Drugs[M].Lyon: International Agency for Research on Cancer, 1990: 77-114.
[106] Yamada T, Mogi M, Kage T, et al. Enhancement by cyclosporin A of metastasis from hamster cheek pouch carcinoma[J]. Arch Oral Biol, 1992, 37:593-596. DOI: 10.1016/0003-9969(92)90143-V
[107] Pistilli B, Bellettini G, Giovannetti E, et al. Chemo-therapy, targeted agents, antiemetics and growth-factors in human milk:how should we counsel cancer patients about breastfeeding?[J]. Cancer Treat Rev, 2013, 39:207-211. DOI: 10.1016/j.ctrv.2012.10.002
[108] Johns DG, Rutherford LD, Leighton PC, et al. Secretion of methotrexate into human milk[J]. Am J Obstet Gynecol, 1972, 112:978-980. DOI: 10.1016/0002-9378(72)90824-1
[109] Gisbert JP. Safety of immunomodulators and biologics for the treatment of inflammatory bowel disease during pregn-ancy and breast-feeding[J]. Inflamm Bowel Dis, 2010, 16:881-895. DOI: 10.1002/ibd.21154
[110] Morton A. Cyclosporine and lactation[J]. Nephrology (Carlton), 2011, 16:249.
[111] Ben-Horin S, Yavzori M, Kopylov U, et al. Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease[J]. J Crohns Colitis, 2011, 5:555-558. DOI: 10.1016/j.crohns.2011.05.006
[112] Kattah MG, Milush JM, Burt T, et al. Anti-TNF and thiopurine therapy in pregnant IBD patients does not signi-ficantly alter a panel of B-cell and T-cell subsets in 1-year-old infants[J]. Clin Transl Gastroenterol, 2018, 9:143. DOI: 10.1038/s41424-018-0018-3
[113] Esteve-Sole A, Deya-Martinez A, Teixido I, et al. Immunological Changes in Blood of Newborns Exposed to Anti-TNF-alpha during Pregnancy[J]. Front Immunol, 2017, 8:1123. DOI: 10.3389/fimmu.2017.01123
[114] Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection[J]. Gastroenterology, 2016, 151:110-119. DOI: 10.1053/j.gastro.2016.04.002
[115] Wieringa JW, Driessen GJ, Van Der Woude CJ.Pregnant women with inflammatory bowel disease:the effects of biologicals on pregnancy, outcome of infants, and the developing immune system[J]. Expert Rev Gastroenterol Hepatol, 2018, 12:811-818. DOI: 10.1080/17474124.2018.1496820
-
期刊类型引用(5)
1. 张兰，周竹娟，程畅，王玉涵，承文超，陈秀英，董开元，黄文. 重庆地区954例中枢神经系统感染性疾病的流行病学和临床特征分析. 解放军医学杂志. 2024(05): 534-541 . 
百度学术
2. 郭路明，于龙，李力韬，吴云峰，李大伟，鲍达，罗展鹏，刘宁，杨尚杰，崔旭. 宏基因组二代测序技术对结核性与非结核性脊柱感染疾病的诊断价值研究. 解放军医学院学报. 2024(05): 457-462+480 . 百度学术
3. 户梦婷，张栋，贾沛瑶，陆旻雅，周梦兰，郭佳钰，苏慧婷，高羿，席婧媛，朱华栋，杨启文. 生食感染广州管圆线虫蜗牛引起嗜酸性粒细胞增多性脑膜炎1例. 协和医学杂志. 2024(06): 1463-1467 . 本站查看
4. 张永杰，王兴华，黄晓岚. 不同抗菌药物方案在中枢神经系统感染性疾病治疗中的应用效果比较. 医药前沿. 2024(29): 28-30+34 . 百度学术
5. 尚远江，邾国庆，张蕾，沈丹丹，潘秋辉. 宏基因组二代测序和传统方法在中枢神经系统感染中的临床应用. 检验医学. 2024(11): 1101-1107 . 百度学术
其他类型引用(2)
计量
- 文章访问数: 371
- HTML全文浏览量: 100
- PDF下载量: 405
- 被引次数: 7
