纸质出版日期:2023-07-20,
收稿日期:2023-03-19
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抗磷脂综合征(APS)是一种与抗磷脂抗体持续存在有关的自身免疫性疾病,其主要特征为血栓形成和妊娠相关疾病的发生。APS可能通过影响卵巢功能、子宫蜕膜化等方式对女性的生殖功能造成不利的影响,并可能在体外受精-胚胎移植(IVF-ET)治疗中引起胚胎种植失败、胚胎种植后的妊娠丢失。常规在不孕人群IVF-ET前进行APS的筛查、治疗尚存在争议,应对患者的风险进行个体化评估,采取相应的管理措施,提高患者的助孕成功率,降低妊娠期母胎风险。本文综述了APS对不孕及IVF助孕结局的影响与人群的管理,为临床诊治提供新思路。
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies, which are associated with thrombosis and pregnancy-related complications. APS may have adverse effects on female reproductive function by affecting ovarian function, endometrialization, and other mechanisms, and may lead to embryo implantation failure and pregnancy loss during in vitro fertilization and embryo transfer (IVF-ET) treatments. The routine screening and management of APS before IVF-ET in infertile populations remains controversial and requires individualized risk assessment and appropriate management measures to improve the success rate of assisted reproductive technologies (ART) and reduce maternal and fetal risks during pregnancy. This review summarizes the effects of APS on female infertility and outcomes of ART, as well as the management of the population affected by APS, providing new insights for clinical diagnosis and treatment.
抗磷脂综合征(antiphospholipid syndrome, APS)是一种自身免疫性疾病,是以血栓形成和/或病理妊娠为主要临床特征,以及实验室检查为持续性抗磷脂抗体阳性的一组症候群,其中产科抗磷脂综合征(obstetric APS,OAPS)的特征包括妊娠 10 周后胎儿丢失、反复早期流产、宫内生长受限或严重的先兆子痫[
抗磷脂抗体包括纳入诊断标准的狼疮抗凝物(lupus anticoagulant, LA)、抗心磷脂抗体(anticardiolipin antibody, ACL)、抗β2糖蛋白I(β2-glycoprotein I,β2GPI),以及一些非标准抗体,包括抗磷脂酰丝氨酸、抗β2糖蛋白Ⅰ结构域I抗体等。2006年悉尼APS的诊断标准(表1)目前使用较为广泛,其包括临床标准和实验室标准,诊断APS必须同时具备至少1项临床标准和至少1项实验室标准,其中临床标准包括:①血管性血栓:任何器官或组织发生≥1次的经客观验证(影像学、组织病理学等)的动脉、静脉或小血管血栓形成。组织病理学如有血栓形成,血栓部位的血管壁无血管炎表现。②病理妊娠:妊娠≥10周,≥1次无法解释的胎儿死亡,且超声或大体提示胎儿形态学正常;妊娠<3周,因子痫或重度子痫前期或严重的胎盘功能不全导致≥1次早产,且胎儿形态学正常;妊娠<10周,连续≥3次不能解释的自然流产。实验室标准包括:①血浆中LA 检测2次阳性,检测时间间隔至少12周;②采用酶联免疫吸附法(ELISA)检测血清或血浆中中高滴度的IgG型/IgM型aCL (IgG型和IgM型分别大于40CPL或MPL,或滴度大于第99百分位数)2次阳性,检测时间间隔至少12周;③用ELISA法检测血清中的中高滴度IgG/IgM型抗β2GPⅠ抗体(滴度>第99百分位数)2次阳性,检测时间间隔至少12周[
由于APS机制及表现具有复杂性,有学者对APS的诊断标准进行了补充,部分aPLs阳性的患者仅符合APS诊断标准中的临床标准或实验室标准,被称为非典型APS。其中产科APS的不典型临床表现包括:连续2次不明原因流产,或3次及以上非连续不明原因流产,或晚发型子痫前期,或胎盘血肿、胎盘早剥、晚期早产[
世界卫生组织将不孕症定义为一年以上未采取任何避孕措施、性生活正常而没有成功妊娠。我国的不孕症患病率约在15%左右[
虽然aPLs影响生育力的致病机制尚不明确,但一些证据提示,它可能与破坏卵母细胞发育和干扰子宫蜕膜化有关,并且已经在体内模型观察到aPLs与蜕膜组织相互作用的证据[
IVF-ET助孕治疗包含了诱导排卵、体外受精、胚胎移植、黄体支持等阶段,目前尚不能明确抗磷脂抗体是否以及如何对其中一个或者几个阶段造成了影响。有实验证据表明,aPLs可能直接作用于滋养层,影响滋养层的分化、成熟,并直接引起细胞损伤、细胞凋亡、人绒毛膜促性腺激素降低,导致植入失败[
APLs的病理作用包括血栓形成、干扰前列环素/血栓素平衡以及滋养层组分之间粘附分子的改变。aPLs诱导的高凝状态引起胎盘梗死和血栓形成,以及螺旋动脉血管病变,从而导致子宫胎盘功能不全,减少母体血液流向绒毛内间隙的正常流量,给胎儿的物质交换造成困难,引起胎儿宫内生长受限,羊水过少,胎儿窘迫,早产或流产[
抗磷脂抗体阳性是妊娠丢失的独立危险因素[
欧洲抗风湿病联盟(EULAR)建议,对于诊断APS的患者妊娠后需要在整个妊娠期间进行随访和干预[
目前临床上对aPL的检测多集中在LA,aCL和抗β2GPⅠ抗体,但一些非标准aPLs同样具有诊断价值。有研究发现,做过两次及以上IVF治疗的患者,三次及以上反复自然流产的患者血清中有着较高的磷脂酰丝氨酸抗体及磷脂酰肌醇抗体[
小剂量阿司匹林(low dose aspirin, LDA)和低分子肝素(low molecular weight heparin, LMWH),在APS引起的产科疾病的治疗中起着举足轻重的作用,它们可以通过抑制胎盘血管中微血栓的形成,抑制炎症反应和促进滋养层细胞的侵袭来改善APS患者的妊娠结局[
APS的药物治疗应该在促排卵阶段开始。血栓性APS 患者可以在开始卵巢刺激时从口服抗凝药物转为低分子肝素皮下注射,并在取卵前12~24 h停用以减少出血并发症,取卵6~12 h后,若患者情况稳定即重新开始使用;产科APS表现或无症状aPLs携带者应从胚胎移植时开始接受低分子肝素,因为黄体期血栓形成风险增加[
自身免疫病患者并不会面临更高的卵巢过度刺激综合征(ovarian hyperstimulationsyndrome,OHSS)的风险,然而,一旦发生OHSS,相关并发症如血栓形成的风险明显增加[
在妊娠前及妊娠期内,对于符合APS诊断标准的患者,应该行APS标准治疗。根据我国2020年产科抗磷脂综合征诊断与处理专家共识,应在妊娠前每天使用小剂量阿司匹林50~100 mg,根据滴度加用羟氯喹每日200~400 mg,并在妊娠期根据个体情况加用低分子肝素[
对于导致不良产科结局的难治性APS的治疗,目前尚缺乏循证医学证据。有学者认为,在常规应用低分子肝素、阿司匹林并加用羟氯喹无效的情况下,低分子肝素、阿司匹林联合 TNF-α拮抗剂可能有机会改善妊娠结局[
综上所述,APS对女性生育力、IVF-ET治疗结局的影响依然存在争议,目前部分研究提示了aPLs的升高可能对IVF的结局有不利影响,然而这些研究大多存在样本量较小且异质性较高的局限性。在IVF治疗前常规进行相关抗体的筛查似乎缺少证据,但患者如果有复发性流产、反复胚胎种植失败及血栓等病史,或者存在发生血栓、不良妊娠的其他危险因素,可行aPLs筛查以期改善IVF治疗结局。对于典型或不典型的APS患者,考虑到可能产生的自然流产、胎死宫内、胎儿生长受限等产科并发症风险,在助孕前及妊娠过程中根据患者具体情况进行单用或联用LDA和LMWH是有意义的,同时应重视多学科会诊,并在孕期加强随访。未来需要开展更多涉及相关机制的基础实验及更大规模、更高质量的临床研究加深对APS与不孕、IVF治疗结局关系的认识,为临床诊治提供新的依据和指导。
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