发布时间： 2025-03-17 15:18:56
反复妊娠丢失（recurrent pregnancy loss, RPL）定义为连续发生两次或两次以上的妊娠丢失。约一半病例没有明确病因，被称为不明原因反复妊娠丢失（unexplained recurrent pregnancy loss，URPL）。母胎免疫功能失调被认为是URPL的病因之一。人类白细胞抗原相容性增加、易感基因、缺乏阻断抗体以及免疫细胞功能失调都会破坏母胎界面的免疫耐受环境。为了纠正母胎免疫失衡，一些免疫疗法已被用于URPL治疗。本综述总结了URPL患者母胎界面免疫微环境的特点和机制，以及相关免疫疗法，为今后的研究提供参考。
反复妊娠丢失（recurrent pregnancy loss, RPL）是一种常见的妊娠早期并发症，以连续多次自然流产为特点。美国生殖医学会（ASRM）将其定义为两次或两次以上临床妊娠丢失，但不强调流产的连续性和孕龄[1]。欧洲人类生殖与胚胎学学会（ESHRE）将其定义为连续发生两次及以上在妊娠24周前的胎儿丢失[2]。总之，RPL的定义尚未统一。关于流产的孕龄、连续性、配偶的同一性以及是否包括生化妊娠仍存争议。
RPL给渴望生育的夫妇带来了巨大的心理压力和经济负担。近年来，RPL的发病率逐年上升，全球约有1%-2%的夫妇受到影响[2]。染色体异常是流产的常见原因。此外，子宫解剖结构异常、内分泌失调、病毒感染、慢性疾病、有害环境暴露，甚至孕妇年龄增加等因素都会增加RPL的风险[3]。然而，经过综合评估后，仍有约一半的RPL病例原因不明，被称为不明原因RPL（unexplained recurrent pregnancy loss，URPL），母胎免疫功能失调可能是URPL的主要机制[4, 5]。
对母体而言，胎儿被视为半异体移植，因此母胎界面的免疫耐受对维持妊娠至关重要[6]。URPL患者存在明显的母胎免疫功能障碍，包括阻断抗体缺乏、免疫细胞异常、细胞因子分泌紊乱、人类白细胞抗原（human leukocyte antigen，HLA）表达异常等[7, 8]。近年来，出现了一些针对URPL的免疫疗法，并呈现出不同的临床表现[9]。本综述以“不明原因的复发性妊娠丢失”、“母胎免疫耐受”和“免疫疗法”为主要关键词，系统检索和整理了截至2024年11月1日在PubMed和Web of Science上的所有相关英文文献。本研究旨在总结URPL母胎免疫调节失调机制的研究进展，以及URPL的潜在免疫疗法。
早期研究认为，持续的免疫抑制是成功妊娠的重要条件。然而，后续研究发现，免疫缺陷和蜕膜内免疫细胞缺乏会影响胚胎着床和胎盘发育[6]。除了蜕膜基质细胞和滋养层细胞，免疫细胞浸润也是母胎界面微环境的重要组成部分。子宫内膜蜕膜化为胚胎着床提供了适宜的环境，随后胎儿绒毛外滋养层细胞（extravillous trophoblasts，EVTs）侵入子宫，将螺旋动脉重塑为扩张的大血管[10]。在这一过程中，免疫细胞也发挥了重要作用。蜕膜自然杀伤细胞（decidual natural killer，dNK）通过分解平滑肌和分泌趋化因子吸引入侵的EVTs，促进螺旋动脉重塑；蜕膜巨噬细胞则负责清除这一过程中产生的凋亡碎片[11]。此后，在妊娠期类固醇激素的影响下，蜕膜组织中的免疫细胞亚群及其分泌的细胞因子发生了一系列生理变化，形成了一个独特的母胎免疫微环境。
妊娠早期，子宫内膜基质细胞和浸润的免疫细胞在着床部位分泌多种炎症因子，包括白细胞介素-6、白细胞介素-8、肿瘤坏死因子α和趋化因子配体1（CXCL1）[12]。子宫内膜活检可诱导炎症反应。研究发现，活检增加了子宫内膜容受性，提示免疫浸润形成的炎症环境是妊娠早期胚胎着床和胎盘形成的重要条件[13]。
胎盘形成后，不同表型和功能的免疫细胞在母胎界面共同建立免疫耐受微环境。其中，蜕膜巨噬细胞主要呈现M2抗炎表型，促进滋养层细胞侵袭和胎儿组织更新。同时吞噬衰老凋亡的滋养层细胞，以防止父系抗原暴露引发的胎儿免疫反应。dNK细胞主要表现为CD56+CD16-表型，细胞毒性较低，通过与CD14+巨噬细胞相互作用，诱导调节性T（Treg）细胞生成，进而抑制免疫反应[15]。此外，Tregs还可调节Th17细胞的数量和功能，发挥抗炎作用[16]。
临产前，胎盘界面的免疫环境再次发生变化。免疫细胞向子宫肌层浸润，有助于促进子宫收缩、分娩和胎盘剥离，这些是分娩做准备的生理过程。促炎性核因子-κB（NF-κB）信号通路是启动分娩和在分娩过程中持续发挥作用的途径[17]。研究发现，在羊膜腔内注射NF-κB抑制肽SN50可推迟怀孕大鼠的分娩时间[18]。一项单细胞RNA测序研究发现，胎儿间充质细胞和母体蜕膜细胞在炎症信号释放中尤为活跃。CXCL、TNF、galectins和IL-6等炎症通路均参与了分娩过程[19]。
主要组织相容性复合体（major histocompatibility complex, MHC）分子是高度多态的蛋白质，主要功能是向抗原特异性T细胞呈递抗原肽[20]。人类MHC分子被称为HLA，分为三类。在正常妊娠期间，父母双方的HLA是不相容的。胚胎携带的父亲HLA会刺激母亲免疫系统产生抗体，从而诱导母胎免疫耐受维持妊娠。EVTs不表达移植过程中同种异体T细胞的主要靶标，包括HLA-A、HLA-B、HLA-DR、HLA-DQ和HLA-DP分子等，反而表达HLA-C、HLA-E、HLA-F和HLA-G分子[20]。
HLA-C分为HLA-C1和HLA-C2两类。杀伤免疫球蛋白样受体（Killer Immunoglobulin-like Receptor，KIR）是HLA-C的受体，主要表达于NK细胞表面[21]。KIR有两种亚型，一个具有激活功能，一个具有抑制功能。HLA-C与NK细胞上的抑制性KIR相互作用可抑制NK细胞的杀伤活性，从而促进EVTs侵袭和胎盘血管重塑[22]。Sharkey等发现，妊娠早期蜕膜组织中表达KIRs的CD56+细胞比例增加，且KIR基因的mRNA表达水平升高[23]。此外，部分蜕膜T细胞亚群表达靶向HLA-C的KIRs[24]。研究表明，T细胞上的KIR受体可抑制TCR介导的活化，并影响其在细胞毒性和细胞因子产生中的作用[20]。
吸收其他HLA I类分子前导序列的肽段，可调节HLA-E在细胞表面的表达[22]。HLA-E是NK细胞上抑制性受体CD94/NKG2A复合物的主要配体。若缺乏源自HLA-I分子的肽段，HLA-E无法呈现至细胞表面，导致细胞更易遭受NK细胞诱导的细胞毒性的影响。此外，HLA-E与CD8+ T细胞上的受体CD94/NKG2C结合，可激活CD8+ T细胞亚群增殖及其功能启动[25]。
HLA-F是一种非经典HLA I类分子，多态性有限，在各种细胞类型中普遍表达。激活dNK细胞上的KIR2DS4，可分泌粒细胞巨噬细胞集落刺激因子等趋化因子，从而促进滋养层细胞侵袭。因此，滋养层细胞中HLA-F表达水平升高，可能是dNK细胞支持胚胎着床的关键机制[26]。
HLA-G是一种低多态性的非经典MHC I类分子，特异性表达于EVTs表面，对建立母胎免疫耐受和维持正常妊娠至关重要。HLA-G与dNK细胞表面的KIR2DL4受体结合后，可上调CXCL10、胎盘生长因子和血管内皮生长因子，促进血管重塑[27]。此外，ILT2与蜕膜树突状细胞（dDCs）上的HLA-G结合时，可上调IL-10和IL-6表达，抑制异体淋巴细胞增殖，促使dDCs分化为耐受性表型[28]。
在正常妊娠中，足月孕妇血清中的阻断因子可阻断父系抗原诱导的母体淋巴细胞增殖20]。这些阻断因子的主要成分是IgG。阻断抗体（又称抗父系淋巴细胞抗体）在妊娠早期开始产生，妊娠头三个月达峰，随后逐渐下降，分娩时再次上升，并随着妊娠次数的增加而增加[29]。研究发现，阻断抗体不仅能覆盖父系异体抗原，阻止免疫识别，还能降低外周血NK细胞比例，推动免疫平衡从Th1型向Th2型偏移[7]。
母胎免疫耐受是成功妊娠的必要条件。在孕早期，蜕膜中含有大量NK细胞，占比>70%，其次是蜕膜巨噬细胞，约占20%-25%。此外，各种T细胞和树突状细胞也参与了蜕膜免疫微环境的形成[10]。
根据分布情况，NK细胞可分为外周NK细胞、dNK细胞和子宫NK细胞。其中，dNK细胞表达一系列特异性识别滋养层细胞表面HLA抗原的受体（如KIR识别HLA-C，CD94/NKG2A识别HLA-E，ILT2识别HLA-G）[14]。EVTs已被证实可以通过其表面的HLA-G分子与dNK细胞上的抑制性受体（KIR2DL4和LILRB）相互作用，从而避免被NK细胞溶解[16]。此外，根据细胞表面标志物的表达，dNK细胞可进一步分为两个亚群：CD56bright CD16- dNK1细胞细胞毒性低，分泌血管内皮生长因子和生长促进因子，促进胎盘发育和胎儿生长；CD56dim CD16+ dNK2细胞分泌多种促炎细胞因子，细胞毒性高，负责检测和抗感染[30]。由dNK1亚型主导的蜕膜环境，对维持母胎界面免疫相容性至关重要[31]。
在对各种信号和刺激做出反应时，巨噬细胞会表现出两种极化形式，即M1和M2，每种极化形式都具有独特的生物学作用。M1巨噬细胞分泌促炎细胞因子，包括IL-1β、IL-6和TNF-α，在调节免疫反应以对抗感染方面发挥着重要作用，但也会导致组织损伤。相反，M2巨噬细胞会产生抗炎细胞因子，包括IL-10和转化生长因子β（TGF-β）。在孕早期，蜕膜巨噬细胞主要是免疫抑制型的M2表型[16]，参与蜕膜重塑、滋养层细胞浸润、血管生成和抑制T细胞活化，对维持免疫平衡和防止过度炎症反应至关重要。
滋养层细胞参与蜕膜巨噬细胞的招募和分化。滋养层细胞通过分泌巨噬细胞集落刺激因子（M-CSF）和IL-10，诱导招募的CD14+单核细胞分化成M2表型[6]。这些巨噬细胞可清除凋亡的滋养层细胞碎片来抑制炎症通路的激活，还会产生吲哚胺2,3-双加氧酶，导致色氨酸降解并抑制T细胞活化[32]。
T细胞是适应性免疫中不可或缺的白细胞，可以分化成Th1、Th2、Th17、Treg细胞等多种亚群。
Th2型细胞因子（如IL-4、IL-5和IL-10）在母胎界面产生，通过调节免疫反应促进胎儿生长和着床，从而维持妊娠。相反，Th1型细胞因子，包括IFN-γ、IL-2和TNF-α，会引发胎儿排斥反应，并阻碍滋养层细胞的增殖和分化，不利于成功妊娠。正常蜕膜免疫结构的特点是Th1/Th2平衡向Th2型偏移[10]。
Th17细胞主要分泌IL-17，在妊娠期参与针对胞外病原体的防御性免疫反应。然而，Th17介导的免疫过度会导致中性粒细胞在母胎界面肆意浸润[33]。Treg细胞分泌与免疫耐受相关的细胞因子，并抑制Th17细胞的过度激活，从而诱导母胎免疫耐受[3]。研究证实，健康妊娠胎盘界面上Th1/Th2和Th17/Treg的比例较低，Th2和Treg细胞分泌的IL-10和TGF-β等细胞因子可诱导母胎界面形成免疫耐受[34]。
虽然临床上并未推荐对URPL患者进行HLA、阻断抗体和免疫细胞等免疫学检测[35, 36]，但大量研究证明它们参与了URPL的发病。本节将讨论这些母胎界面免疫变化的最新研究成果。
目前，MHC和易感基因理论被认为可以部分解释URPL的发病机制。配偶间HLA基因位点相容性增加可能导致阻断抗体无法产生。临床研究发现，共享两个或以上HLA等位基因的夫妇，RPL风险升高[37]。一项荟萃分析表明，虽然RPL夫妇与对照夫妇在HLA-A、-B和-C位点的等位基因共享方面无显著差异，但RPL夫妇在HLA-DR位点的等位基因共享显著增加，表明HLA-DR相容性与RPL风险之间存在潜在关联[38]。
此外，母体易感基因位点可能导致对胚胎抗原的免疫反应不足。在一项涉及高加索人群的病例对照研究中，HLA-DRB1*03被确定为RPL的易感等位基因[39]。在台湾人群中，HLA-DRB1*07和HLA-B13的频率较高[37]。HLA DQ2/DQ8的表达可影响子宫内膜微生物群组成，增加了RPL患者患乳糜泻的易感性[40-42]。最近的一项大规模GWAS分析探讨了全基因组罕见拷贝数变异对URPL易感性的影响[43]，发现HLA-C变异与URPL风险的关系最为显著。单倍型HLA-C*12:02、HLA-B*52:01和HLA-DRB1*15:02具有明显的保护作用。然而，cadherin11基因罕见功能缺失变异与URPL风险有关。
除MHC和易感基因理论外，HLA-C/HLA-G与RPL的关联也在研究中[7]。HLA-C2与抑制性KIR的匹配，以及HLA-G基因14 bp插入可能与URPL有关[44，45]。然而，HLA多态性与RPL患者妊娠结局的关联仍未充分探究。目前，仅推荐对生育男婴后出现继发性RPL的北欧妇女，进行HLA II类分型（HLA-DRB1*15:01、HLA-DRB1*07和HLA-DQB1*05:01/05:2），以评估预后[35]。
一项研究显示，成功妊娠的RPL妇女中阻断抗体阳性率（82.4%）明显高于流产组（10%）。母体混合淋巴细胞反应（MLR）阻断因子因针对精子中滋养层-淋巴细胞交叉反应抗原（TLX）而产生，与HLA分子和滋养层抗原具有交叉反应性，附着于滋养层细胞上的Fc片段受体，可保护胚胎免受免疫攻击[8]。此外，研究发现MLR阻断抗体主要属于免疫球蛋白G-3亚类，在妊娠期间自然产生，也可通过RPL妇女的免疫治疗诱导产生，进而促进成功妊娠[46]。然而，Jablonowska等发现，妊娠前阻断抗体阳性与RPL患者的妊娠结局无关[47]。尽管目前临床实践中并不常规检测阻断抗体，但在大多数调查RPL免疫疗法疗效的研究中，仍将其作为常规检测指标，用于评估治疗效果[48-50]。
蜕膜化异常可能是许多女性URPL病例的关键因素。免疫细胞，如NK细胞、巨噬细胞和T细胞，在蜕膜化过程中发挥关键作用。研究表明，RPL患者蜕膜组织内这些免疫细胞的组成和功能均出现失调[51]。此外，在RPL患者的子宫内膜中发现炎性小体的表达明显增加[52, 53]。目前，指南仅提及在RPL中应用NK细胞检测，但并不推荐[35]。
单细胞RNA测序分析显示，RPL患者样本中促进胚胎发育的dNK亚群（dNK1）比例降低，而具有细胞杀伤和免疫反应性的dNK亚群（dNK2）则显著升高[30]。此外，CXCR4+ CD56 bright dNK细胞显示出较低的活化和细胞毒性表型。在RPL患者中，这些细胞的数量明显减少，且促进Th2分化的能力较弱[54]。NK细胞的活化与Tim-3的表达有关。约60%的dNK细胞表达Tim-3，并增加IL-4分泌、减少TNF-α和穿孔素[55]。既往研究表明，RPL患者的Tim-3+ dNK细胞比例减少。Tim-3在妊娠期间通过影响细胞因子分泌和抑制细胞毒性，对NK细胞发挥调节作用[9]。此外，肠道通透性增加可能是导致RPL免疫异常的机制之一[56，57]。肠道微生物群可能会通过诱导免疫反应影响NK细胞功能，进一步加剧子宫内膜免疫环境的失衡。
目前已在外周血、孕前子宫内膜或流产后蜕膜组织中检测到NK细胞[58，59]。然而，不同样本来源的NK细胞亚群频率存在显著差异。相对而言，在子宫内膜或蜕膜组织样本中检测NK细胞的准确率较高，但由于缺乏标准化检测程序和检测标准，并不适合临床应用。
M-CSF和IL-10是人类蜕膜中M2巨噬细胞的强诱导因子。在RPL患者中，血清M-CSF浓度显著低于健康个体[60]。RPL妇女蜕膜中M1巨噬细胞的招募量大于M2巨噬细胞，与正常妊娠相反[61]。此外，RPL患者表现出细胞因子失衡，有利于向M1巨噬细胞极化。例如，胰岛素样生长因子II mRNA结合蛋白3在RPL病例的胎盘绒毛样本中低表达，这可以激活滋养层细胞中的NF-κB通路，抑制IL-10表达，最终促进M1巨噬细胞的极化[62]。
T细胞相关因素可能参与URPL的发病机制，如CD4+/CD8+比率异常、CD4+ T细胞平衡向Th1偏移、Treg数量减少、免疫抑制功能减弱以及Th17细胞和Treg细胞失衡[9]。
人类蜕膜表达Galectin-9，它通过抑制T细胞活性、抑制Th1型细胞因子释放和促进CD4+CD25+Foxp3+ Treg细胞增殖来调节免疫反应[63]。Galectin-9具有多种生物学功能，对皮肤病变中的Th1/Th2免疫偏差有显著影响。在RPL中，胎盘中Galectin-9的表达明显减少，从而促进了Th1细胞的分化[64]。
最近的研究发现，Th17和Treg细胞比例失衡在URPL中发挥重要作用。Th17细胞分泌的IL-17和IL23可与Th1亚群协同介导组织炎症和免疫反应[3]。Wang等人发现，在URPL患者中，Treg细胞对Th17细胞活性的抑制作用减弱，表明Treg/Th17平衡向Th17占优的方向偏移[65]。研究表明，URPL妇女外周血中CD4+ CD25+细胞的比例显著低于正常妊娠早期妇女。此外，有报道称URPL患者存在Treg细胞功能缺陷[66]。循环CD4+ CD25+ Foxp3+ Treg细胞数量减少，甚至可以作为有流产史孕妇再次流产风险的指标。
淋巴细胞免疫疗法（lymphocyte immunotherapy，LIT）由Mowbray等人提出[67]，是一种针对URPL的主动免疫疗法。淋巴细胞免疫疗法主要是指从男性伴侣或无血缘关系的捐献者身上抽取静脉血，分离淋巴细胞，然后按照特定的治疗方案静脉注射淋巴细胞。迄今为止，LIT是针对RPL研究最为广泛的免疫干预方法。LIT可以诱导URPL患者产生保护性抗体，如抗父系细胞毒性抗体、MLR阻断因子、抗独特型抗体和孕酮诱导阻断因子等[16]。此外，LIT还能显著降低Th1和Th17细胞水平，提高Th2和Treg细胞水平，从而导致IL-10和TGFβ的表达增强，这对维持妊娠期免疫耐受至关重要[68]。
Liu等人发现，LIT可显著提高URPL患者的活产率，其中年龄较小和阻断抗体阳性是LIT成功的独立因素[49]。他们还进行了一项包括18项随机对照试验的荟萃分析，结果显示在妊娠前及妊娠期间给予LIT的疗效优于仅在妊娠前给予LIT。此外，单次治疗的剂量较低（尤其是少于1亿个淋巴细胞或100毫升外周血）时，往往能取得更优结果[69]。然而，目前关于LIT的用药剂量、途径和时间尚未达成共识[50, 70-72]。在治疗过程中，患者可能出现局部反应（如注射部位发红、压痕）甚至血源性感染[73]。目前，ESHRE指南不建议对URPL患者常规进行LIT，但阻断抗体检测阴性的患者可考虑接受LIT治疗[3]。
静脉注射免疫球蛋白（intravenous immunoglobulin, IVIG）是一种多克隆免疫球蛋白G的血浆制品，临床上用于治疗体液免疫缺陷和自身免疫性疾病。IVIG可通过减少细胞毒性T细胞和NK细胞、维持Th1/Th2平衡以及促进免疫抑制细胞因子（包括IL-10和TGF-β）的合成来调节免疫反应[16，74]。一项研究在妊娠32周前为RPL患者注射IVIG（400mg/kg，每4周一次），结果显示，IVIG治疗可减轻Treg细胞的衰竭表型，从而改善妊娠预后[75]。另一项针对URPL患者的临床研究发现，IVIG治疗组（87.5%）的活产率高于安慰剂组（41.6%）[74]。此外，继发性RPL患者可能从IVIG治疗中获益更多[76，77]。然而，由于用药时间和剂量的差异，研究结果存在争议。费用高昂、潜在副作用和适应症不明确等也限制了IVIG在RPL患者中的应用。
脂肪乳剂是一种肠外营养制剂，可抑制NK细胞功能和炎性细胞因子的释放，体外研究已证实其具有免疫调节特性。临床研究证明，它对URPL和反复着床失败（RIF）患者有效，尤其是对NK细胞活性异常的患者[78]。一些研究提供了中等程度的证据，表明静脉注射脂肪乳剂疗法可改善URPL妇女的生殖结局，尤其是活产率[79-81]。与IVIG相比，脂肪乳剂可能是一种更安全、更具成本效益的治疗方案[82]。然而，部分研究报告了大剂量静脉注射后的严重不良反应，如急性肾损伤；且现有研究质量不高，存在显著异质性。因此，仍需进一步研究以确定脂肪乳剂在临床中的疗效和安全性。
富血小板血浆（platelet-rich plasma, PRP）是从外周血中提取的血液浓缩物，其中血小板浓度至少是基线水平的35倍。它还包括一些细胞因子，如TGF-β和IL-1β[83]。PRP在膝关节骨关节炎和勃起功能障碍等领域广泛应用，通过调节细胞增殖、趋化和细胞因子分泌发挥重要作用。Li等人发现，在不明原因RIF患者中，PRP组的活产率、临床妊娠率和着床率显著高于安慰剂组[84]。一项网络荟萃分析也显示，宫腔内注射人绒毛膜促性腺激素、粒细胞集落刺激因子、外周血单核细胞和PRP均能显著改善RIF患者的临床妊娠和活产率，其中PRP的效果最佳[85]。然而，关于PRP在URPL患者中的应用，相关研究较为有限。
环孢素A（Cyclosporine A, CsA）是一种免疫抑制剂，在妊娠期器官移植患者中被证实是安全的[86]。此外，对新生儿出生后的随访显示，其生长发育、免疫功能及其他方面均无异常[87]。在妊娠早期使用低剂量CsA可促进胎盘界面滋养层细胞的增殖、迁移和侵袭，从而促进胚胎着床[88]。同时，CsA可降低RPL患者的Th1/Th2比率，并促进IL-10和其他Th2型细胞因子的分泌，维持母胎免疫耐受[89]。Ling等人的研究进一步表明，小剂量CSA可提高URPL患者的活产率，且未出现母体或新生儿相关并发症[90]。
他克莫司也是一种常用的免疫抑制剂。在一项随机对照试验中，对于外周血中IL-33/ST2水平升高或Th1/Th2细胞比例升高的难治性RPL患者，他克莫司显示出潜在治疗价值[91]。在另一项针对RIF患者的试验中，从胚胎移植前2天开始给予他克莫司1-3 mg/d，持续至妊娠试验共16天，显著改善了妊娠结局[92]。西罗莫司（又称雷帕霉素）最初于20世纪70年代作为低毒性抗真菌药物开发，后因具有免疫抑制作用被用于预防器官移植排异反应[93]。在小鼠模型中，西罗莫司可逆转Treg细胞数量下降，提示其对Treg水平下降的URPL患者具有潜在治疗价值[94]。鉴于CsA对滋养层细胞具有剂量依赖性双重作用，且对后代的长期影响尚不明确，适当的剂量和标准化的治疗时间对确保成功妊娠和减少不良反应至关重要，这一点同样适用于其他免疫抑制剂。目前，指南仅建议确诊自身免疫性疾病的RPL患者使用免疫抑制剂[35, 36]。
TNF-α是全身炎症的标志物，在RPL患者的外周血浆中高表达[95]。TNF-α抑制剂是一类新型生物制剂，主要治疗类风湿性关节炎、炎症性肠病和其他以慢性炎症为特征的疾病。一项针对75名RPL/RIF患者的回顾性研究发现，阿达木单抗（一种TNF-α抑制剂）联合IVIG治疗能有效提高活产率，且效果优于单独使用抗凝疗法（肝素和阿司匹林）[96]。
依那西普是另一种TNF-α抑制剂，常用作抗风湿药。一项随机对照试验证实了依那西普对难治性URPL患者的有效性。在妊娠第4周至第10周，依那西普能显著降低患者的血浆TNF-α水平和pNK细胞活性[97, 98]。对于现有治疗方案无效的难治性URPL患者，依那西普可能是一种选择。然而，由于缺乏高质量研究支持，其在妊娠期的安全性尚未确定。
合成皮质类固醇（如泼尼松）对Th1/Th2细胞因子和NK细胞有免疫抑制作用，被认为是潜在的治疗方法[9]。研究表明，泼尼松使用与RPL患者uNK细胞水平下降有关[99]。因此，相比于uNK细胞计数正常的患者，uNK细胞计数异常的URPL患者在接受糖皮质激素治疗后，生育结局有所改善[99，100]。然而，长期或大剂量使用皮质类固醇会增加患者罹患高血压和糖尿病的风险。目前，糖皮质激素治疗的最佳时机、剂量和疗程仍在探索中，亟需开展大样本随机对照研究以制定循证指南。此外，进一步研究URPL患者的免疫生物标志物，对于指导糖皮质激素治疗至关重要[99, 101, 102]。
维生素D属于类固醇激素，具有抗炎特性，通过抑制T细胞增殖和细胞因子合成，可下调IL-2、IFN-γ和TNF-α等炎症基因转录[16]。维生素D不足与流产风险增加有关，补充维生素D可能有助于预防RPL[103-105]。在RPL患者中，维生素D不足患者的外周血中CD56+细胞毒性NK细胞活性及Th17/Treg比率显著高于维生素D充足者[106，107]。一项临床研究发现，URPL患者补充维生素D可降低外周血中Th、B和NK细胞以及IL2、TNF-α和IFN-γ的水平，同时增加IL-4和IL-10[108]。这些变化可能有助于促进成功妊娠。此外，无论是否患有RPL，维生素D补充剂已成为孕妇的常用处方。
孕酮对维持正常妊娠至关重要，作用机制包括促进免疫耐受、增加子宫血流量和增强子宫内膜容受性。体外实验发现，孕酮可下调Th1细胞释放的细胞因子，同时促进Th2细胞分泌细胞因子[109]。此外，孕酮还能激活淋巴细胞合成孕酮诱导的阻断因子，该因子能介导母胎界面的免疫耐受，抑制NK细胞的活性，从而对胎儿产生保护作用[110]。此外，多项研究表明，孕酮可诱导HLA-G的表达[111]。
多项临床研究调查了孕酮在URPL患者中的作用，结果存在争议[112-116]。一项荟萃分析表明，补充孕酮治疗可能会降低URPL患者后续妊娠的流产率[117]。然而，一项针对836名妇女进行的多中心随机试验发现，在妊娠试验呈阳性后，使用阴道微粒化孕酮的URPL妇女与使用安慰剂的妇女在活产率方面无显著差异[113]。目前，国际妇产科联盟不建议URPL患者在妊娠试验呈阳性时开始使用阴道天然孕酮。相反，ESHRE指南建议，从黄体期开始服用孕酮，而不是等到妊娠试验呈阳性后再服用，可能获益更多[35]。口服合成孕酮可能有一定效果，但需要大量安慰剂对照试验来确定其最佳使用时机和剂量[118]。
蜕膜细胞释放的G-CSF支持中性粒细胞的增殖和分化。有证据表明，G-CSF具有免疫调节特性，能够诱导外周Treg细胞和髓源性抑制细胞的功能。它还能增强蜕膜巨噬细胞对血管内皮生长因子的表达，促进血管重塑[119]。此外，体内实验证明，给予G-CSF可改善子宫内膜厚度和卵母细胞质量，可能促进胚胎着床[120]。在一项涉及68名URPL妇女的单中心研究中，G-CSF治疗组的活产率（82.8%）明显高于安慰剂组（48.5%）[121]。此外，与IVIG或抗凝治疗相比，G-CSF可能是一种更有效的治疗方案[122]。然而，Eapen等人发现，rhG-CSF组的不良反应发生率（68.4% vs. 58.1%）和新生儿先天畸形率（2.1% vs. 2.0%）更高[123]。尽管G-CSF有治疗RPL的潜力，但在推荐其用于临床实践之前，仍需在不同人群中进行更多高质量的试验以确认其疗效。
母胎界面的免疫失衡是导致URPL的重要潜在机制。胎儿滋养层细胞、母体蜕膜基质细胞和免疫细胞共同组成了一个复杂、有序、动态变化的分子调控网络。事实上，这些成分的功能障碍或干扰都有可能导致RPL的发生。为了改善URPL患者的妊娠结局，多种免疫疗法被提出并应用，如LIT、IVIG、脂肪乳剂等。然而，由于研究人群和方法的异质性，研究结果尚未定论。未来需要开展大样本、多中心研究，为URPL患者的免疫疗法提供高质量的证据。
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