探索反复妊娠丢失和反复着床失败的免疫学因素及治疗

发布时间： 2025-03-07 10:38:35

探索反复妊娠丢失和反复着床失败的免疫学因素及治疗

Jenny Valentina Garmendia¹, Claudia Valentina De Sanctis¹, Marián Hajdúch^1,2,3, Juan Bautista De Sanctis^1,2,*

摘要

反复妊娠丢失（Recurrent pregnancy loss，RPL）是指在妊娠24周前发生两次及以上的连续流产，影响了3-5%尝试怀孕的女性。RPL病因复杂，常导致心理困扰和生活质量下降。相比之下，反复着床失败（recurrent implantation failure，RIF）是指在三次或更多次高质量胚胎移植或至少两次卵子捐赠后未能成功怀孕。RIF与RPL有一些共同的致病因素。两者的免疫学因素涉及子宫NK细胞改变、M2巨噬细胞和髓源性抑制细胞减少、Th1/Th2比值增加、Treg/Th17比值降低、伴侣共享HLA等位基因≥3以及自身免疫性疾病。目前对于这些免疫学机制，治疗方法多样，疗效不一，尚存争议。本综述旨在探讨与RPL和RIF相关的免疫因素和相应的免疫治疗，包括类固醇、静脉注射免疫球蛋白、钙调神经酶抑制剂、抗TNF抗体、脂肪乳输注、粒细胞集落刺激因子和淋巴细胞免疫治疗。

关键词：反复妊娠丢失；反复着床失败；NK细胞；调节性T细胞；Th17；Th1；Th2；巨噬细胞；细胞因子；HLA

1. 前言

反复妊娠丢失（recurrent pregnancy loss, RPL）或复发性自然流产（recurrent spontaneous abortion, RSA）的定义尚不统一：美国妇产科学会及欧洲人类生殖与胚胎学会（ESHRE）RPL指南工作组将其定义为妊娠20周（或24周）前连续发生两次及以上妊娠丢失，而世界卫生组织则定义为三次及以上妊娠丢失[1-4]。该病症影响约3-5%的育龄女性[1-4]。RPL可分为原发性（无成功妊娠史）和继发性（有成功妊娠史）两类[1-4]。患者后续成功妊娠的概率与年龄及既往流产次数密切相关[1-4]。RPL的病理生理机制复杂，涉及母体与胎儿多因素交互作用[1]。危险因素包括内分泌功能异常、子宫器质性病变（畸形、息肉、肌瘤及宫腔粘连）、输卵管积水、胚胎染色体异常、子宫内膜功能障碍、子宫内膜异位症、血栓前状态、慢性应激、高体重指数、男性因素（精子质量）、感染及免疫异常等[5-9]。与其他妊娠相关疾病类似，RPL以母胎免疫耐受失衡为特征[10]。此外，约50%的病例病因不明，被称为“特发性RPL”[11]。

反复着床失败（recurrent implantation failure, RIF）被定义为三次及以上优质胚胎，或两次及以上卵母细胞捐赠移植后未能实现胚胎着床[12]。RIF与RPL有着类似的病因，包括高龄、父母双方吸烟史、高体重指数、应激状态、阴道菌群失调、免疫异常（细胞因子水平异常及自身抗体阳性）、慢性子宫内膜炎、输卵管积水、子宫内膜息肉、子宫肌瘤、子宫先天性解剖异常、配子及胚胎质量异常（遗传及表观遗传因素）、子宫内膜容受性下降、维生素D缺乏及基因多态性（HLA-G、p53、VEGF）等[12-19]。研究还发现miRNA及长链非编码RNA（lcnRNA）可能参与其发病机制[20-22]。

免疫系统在胚胎正常着床、母胎交互及胚胎发育过程中发挥关键调控作用[23]，因此免疫异常可能是RPL与RIF的共同病理基础。此外，阴道菌群失调（vaginal dysbiosis, VD）也会损害局部免疫反应，与流产、早产和体外受精（in vitro fertilization，IVF）不良结局等妊娠并发症有关。子宫内膜中的非乳酸杆菌主导的微生物群与胚胎着床率、持续妊娠率及活产率降低显著相关[16,23-26]。

RPL患者自然受孕后发生妊娠并发症的风险显著增高，包括妊娠期糖尿病、先兆子痫、前置胎盘、胎盘早剥、流产、早产、剖宫产、围产期死亡及新生儿重症监护需求等[27,28]。RPL也是长期心血管疾病和静脉血栓栓塞的预测指标。研究显示，与既往着床成功者相比，既往着床失败患者后续妊娠早期自然流产的风险显著升高[29]。即使移植整倍体囊胚，单次胚胎移植的活产率仍仅为50-60%[30]。

RPL还与心理发病率、夫妇生活质量差和婚姻问题更多有关[31]，因为这对夫妻和临床医生来说都非常令人沮丧[32]。流产的心理后果包括夫妻双方焦虑、抑郁、创伤后应激障碍和自杀倾向增加[33,34]。这些心理状况可能会影响激素和昼夜节律以及免疫反应[35]。

本文系统综述免疫因素在RPL与RIF发病中的作用机制，并探讨相应的免疫干预策略。

2. RPL和RIF中的先天免疫反应

先天免疫反应是抵御病原体的首道防线，涉及吞噬作用、内吞作用、分泌溶解颗粒和保护肽以及释放促炎细胞因子、趋化因子、脂质酶、代谢物、氮和氧自由基等机制，在炎症过程中起着关键作用[36]。此外，先天免疫有助于组织稳态和重塑。随后将分析描述参与妊娠，RIF和RPL的免疫细胞。表1概括了免疫细胞和免疫反应。

表1. RPL相关的免疫细胞

细胞类型	生理功能	与RPL相关的功能障碍	参考文献
先天免疫	不涉及抗原呈递的免疫反应		[36]
NK细胞	清除异常细胞和病原体。子宫及蜕膜NK细胞的胎儿耐受反应区别于外周NK细胞。	耐受性降低，细胞毒性反应增强。	[37–57]
NKT细胞	清除异常细胞和病原体。	细胞毒性功能增强，参与局部炎症。	[67,69]
Τγδ细胞	调控组织稳态、吞噬病原体及抗原呈递。	细胞毒性增强，参与局部炎症反应。	[70,71]
巨噬细胞	存在于子宫中，参与耐受性应答。	促炎反应，分泌细胞毒性细胞因子，增加活性氧/氮物质。	[72-79]
树突状细胞	高效抗原呈递。	抗原表达异常。	[80-85]
肥大细胞	存在于子宫内膜中。	异常激活并发挥促炎作用。	[86-90]
嗜酸性粒细胞	在激素周期特定阶段存在于子宫内膜。	作用未知。	[92,93]
适应性免疫	需抗原呈递，具有高度选择性		[36]
细胞毒性T细胞 Th1	清除异常细胞。促炎反应。激活B细胞。IgG产生。	参与胎儿排斥。	[97-99] [101,102]
Th2	抗过敏反应。激活B细胞。IgE产生。	拮抗Th1作用。	[101,102]
Th17	促炎反应。	胎儿排斥，诱导中性粒细胞迁移。	[106,107]
调节性T细胞（Treg）	对胎儿产生免疫耐受作用。	数量减少，促进Th1及细胞毒性功能。	[103,108,119]
B细胞	B1细胞分泌针对病原体的IgM并保护组织。	子宫内膜中B1细胞减少、B2细胞增多，可能产生自身抗体。	[121-126]
髓系抑制细胞（MDSC）	M-MDSC和PM-MDSC参与组织耐受性应答。	子宫内膜中数量异常。	[127-134]

2.1. 自然杀伤（Natural Killer，NK）细胞

NK细胞是大颗粒状的淋巴细胞，不含抗原T细胞受体（antigen T cell receptor，TCR）或B细胞受体（B cell receptor，BCR）[37,38]，分为两种亚型：CD56dim/CD 16+（pNK）和CD56bright/CD16−（uNK）[36]。pNKs存在于外周血中，具有较强的细胞毒性；uNKs存在于子宫中，产生更多的细胞因子并具有调节功能[37,38]。此外，还存在子宫内膜eNK和蜕膜dNK细胞[37]。不同的亚群的免疫调节活性不同[37]。怀孕前，eNK细胞占子宫内膜淋巴细胞总数的30%，dNK细胞占蜕膜淋巴细胞总数的70%。dNK细胞产生血管生成素-2、胎盘生长因子和血管内皮生长因子，表达NKD2G、NKp44、NKp46和NKp30[37-39]。

大多数RPL患者存在NK细胞活性异常，外周血NK细胞水平显著高于对照组[37,39,40]。RIF女性的外周血NK细胞数量（在淋巴细胞计数中占比>18%）显著高于可育对照组，NK细胞（CD56dim/CD69+）高度活化[40,41]。在RPL女性患者中，即使总细胞群保持不变，细胞毒性CD56dim亚型数量增加，而CD56bright细胞数量减少[37,42]。外周血NK细胞的活化水平（CD69+）可以预测妊娠结局[43-46]。1型细胞因子（如IL-1、IL-2和TNF-α）可增加uNK细胞上CD16的表达，并诱导对滋养层细胞的细胞毒性[47]。与RPL和RIF患者相比，可育非孕女性和正常孕妇的NK细胞毒性反应均显著降低（流式细胞术检测，效应细胞与靶细胞比率为50:1）[48]。

多项研究表明，子宫uNK细胞群增加与RPL和RIF之间存在关联[49,50]。据报道，在特发性RIF女性中，黄体中期子宫内膜CD56+细胞的频率显著更高[49,50]。然而，另一项研究显示uNK细胞计数与RPL病理之间并无相关性[51]。

一般认为，RPL女性可能存在子宫内膜NK细胞募集不受控制，和/或CD56dim细胞向细胞毒性较低的CD56bright细胞转化失败[37,52]。然而，一项关于uNK细胞的荟萃分析显示，RPL女性患者较对照组无显著差异[53]。在正常蜕膜和子宫内膜中占主导的CD16−CD56bright NK细胞亚群在RPL患者中显著减少，取而代之的是CD16+CD56dim NK细胞[54]。此外，胚胎移植失败组移植日外周血中CD56+细胞和CD16+CD56+细胞的百分比，显著高于接受静脉免疫球蛋白治疗后进行IVF的不孕妇女植入组[55]。在子宫内膜中，与分娩组相比，流产组CD16+CD56dim细胞百分比显著升高，CD16−CD56bright细胞百分比显著降低[56]。Strobel等[57]表明，继发性RPL患者的循环CD56dimCD16brightNKG2D+和CD56dimCD16brightNKp46+的数量低于对照组，表明细胞毒性受体也至关重要。

在特发性RPL或着床失败的未孕女性中，CD56bright pNK细胞内IFN-γ/TNF-α（定义为NK1或炎症型）增加，IL-4/IL-10（定义为NK2或抗炎型）减少[58]。复发性流产孕妇的NK1/NK2比值较高，表明子宫内膜处于促炎环境，这对妊娠不利[6,39]。此外，NK-CD8表达增加（>60%）可预测IVF失败，而表达降低（<40%）可显著预测后续妊娠失败[44]。NK-CD8+高表达与NK细胞频率增加、NK细胞毒性增强和CD158a表达上调有关[44]。在RPL或着床失败的女性中，CD56bright NK细胞上天然细胞毒性受体（NKp46、NKp44、NKp30）和a2V-ATP酶的表达水平，与CD56dim NK细胞相比显著上调[58]。天然细胞毒性受体和a2V-ATP酶在NK细胞亚群中的表达差异，可能提示RPL和着床失败患者存在NK细胞毒性及细胞因子分泌失调[58]。

母体KIR与绒毛外滋养层细胞表达的HLA I类分子之间的相互作用，对于胚胎着床和子宫螺旋小动脉重塑至关重要[59]。KIR和HLA的多态性可影响NK细胞反应性，并与复发性流产和先兆子痫的易感性有关。RPL患者KIR 2DL2表达增加[60]，且当HLA-C2等位基因频率升高时，相关性更强[61]。一项荟萃分析显示，KIR2DS2和KIR2DS3是RPL的重要危险因素，而抑制基因KIR3DL1是保护因素[62]。RPL女性中普遍存在缺乏激活KIR的KIR AA单倍型[63-66]。此外，携带KIR AA单体型的患者在接受IVF治疗时，较自然妊娠者流产风险显著增加[67]。当胎儿携带HLA C2C2且母体为KIR AA单体型时，与胚胎着床失败、复发性流产及先兆子痫显著相关[62]。蜕膜NK细胞和滋养层细胞中之间激活性和抑制性信号的平衡可能是影响胚胎着床的重要因素[67]。另一项研究发现，在整倍体单胚胎移植后，KIR A单倍型携带者较KIR B单倍型携带者妊娠丢失率更低。然而，当胚胎存在HLA-C等位基因时，风险模式发生改变：高危组合（KIR A+纯合子C2和KIR B+纯合子C1）的丢失风险较其他组合增加了51%[67]。

在RPL患者中，表达CD3和CD56标志物的NKT细胞增加[67-69]。此外，Xu及其同事发现Tγδ细胞可能在这一过程中发挥作用[70]。这些细胞在绒毛膜促性腺激素刺激下可分泌IL-10[71]。然而，由于潜在亚群的复杂性和循环细胞数量较少，NKT和Tγδ细胞在RIF和RPL中的作用尚未明确。该一领域需要更多的研究。

2.2. 巨噬细胞和树突状细胞

在怀孕期间，巨噬细胞和Treg细胞共同维持母胎免疫耐受。巨噬细胞可以改变蜕膜微环境，从而促进RIF和RPL[72]。巨噬细胞主要有两个亚群：M1（经典激活，诱导炎症并激活免疫）和M2（替代激活，抑制炎症）。在黄体期和健康妊娠期间，M2型巨噬细胞在子宫内膜中丰富。M1/M2巨噬细胞比值失衡可导致先兆子痫、宫内生长受限、RPL和RIF等并发症[72-76]。不明原因RPL患者与对照组相比，蜕膜中的巨噬细胞CD80和CD86（共刺激分子）表达水平升高，IL-10表达降低。Treg细胞可抑制巨噬细胞CD80、CD86和IFN-γ的表达，同时增加IL-10的表达[76]。RPL患者子宫内膜中的巨噬细胞（用CD14标记）显著高于对照组[76-79]。在RIF患者中，与轻度局灶性子宫腺肌病或无病变者相比，弥漫性子宫腺肌病（子宫内膜组织在子宫肌层中）与子宫内膜基质中巨噬细胞和自然杀伤细胞密度显著增加有关[79]。

树突状细胞（dendritic cells，DC）通过调节免疫反应和参与组织重塑，在胚胎着床中发挥关键作用[80,81]。DCs通过呈现耐受性表型并分泌吲哚胺2,3-双加氧酶，促进Treg细胞增殖，同时降低Th1细胞存活率和CD8+ T细胞毒活性[80,81]。子宫DCs表面CD80/86复合物下调可导致T细胞无反应，从而维持胎儿免疫耐受。在着床过程中，人工耗竭DC或高度炎症环境与着床失败有关[80,81]。与可育对照组相比，RIF/RPL患者外周血和子宫内膜中ILT4+DC的频率较低[82]。同时，RPL患者蜕膜和外周血浆细胞样树突状细胞减少[83]。另一方面，RPL患者外周血总DCs和髓系DCs数量显著高于对照组[84]。另一项研究显示，妊娠早期RPL患者的外周DCs与对照组无显著差异[85]。

DCs抗原呈递异常不仅可能导致着床失败和胎儿排斥反应，还可能导致自身免疫性疾病。

2.3. 多形核细胞

子宫内膜肥大细胞作为组织免疫细胞的重要组成部分，在子宫内膜组织生理学和病理学中发挥作用[86,87]。肥大细胞与女性生殖系统中的巨噬细胞相互作用[88]。它们在RPL中增加[89]，并在子宫内膜异位症中对雌激素高度敏感[90]。由于巨噬细胞-集落刺激因子1受体（colony stimulating factor 1 receptor，CSF1R）和肥大/干细胞生长因子受体KIT在子宫内膜异位病变中过表达，近期研究表明酪氨酸激酶抑制剂pexidartinib治疗可减轻子宫内膜组织的炎症反应[91]。

嗜酸性粒细胞在正常子宫内膜中含量极少，但在子宫内膜异位症中显著存在，并参与组织修复和重塑[92]。其迁移过程主要受趋化因子水平升高驱动[93]。月经排出物的炎症特征中亦检测到相关趋化因子[94]，提示在正常激素周期中嗜酸性粒细胞可能短暂迁移至组织中。他们在RIF和RPL中的作用尚不清楚。

非月经期，正常子宫内膜中不存在中性粒细胞[95]。然而，感染、损伤等炎症性疾病会募集中性粒细胞，同时趋化因子和IL-17增加会影响子宫内膜组织，阻碍着床、胎儿存活和诱发先兆子痫/子痫[96]。

2.4. T细胞

T淋巴细胞是适应性免疫的关键要素。其中，辅助性T细胞（CD3+/CD4+）细胞和抑制/细胞毒T细胞（CD3+/CD8+）两大亚群，在胎儿抗原识别和局部免疫调节中发挥重要作用[11]。Th1、Th2和Th17之间的平衡，指导妊娠期的免疫反应[37,39,42]。

RPL患者子宫内膜中CD8+ T淋巴细胞的比例显著降低，CD4+/CD8+比值增加[54]。相反，RPL女性外周血中CD8+ T细胞百分比显著高于健康对照组，而CD4+/CD8+比值显著降低[97]。此外，在流产病例中，缺乏PD-1表达的蜕膜效应记忆CD8+细胞的总比例升高[98]。

RPL女性中枢记忆性CD4+T细胞和CD8+DR+T细胞（活化的细胞毒性细胞）的绝对计数显著升高[99]。RIF患者淋巴细胞中NKG2D+ γδ T细胞频率与活产率呈负相关[100]。在一项遗传研究中，RIF组子宫内膜活化记忆CD4+ T细胞的比例升高，而γδ T细胞的比例降低[101]。

RPL女性T细胞受体的可变TCR beta（BV）链19频率较对照组升高，而BV5.2的频率降低，表明TCR-BV的特异性偏移使用可能与RPL易感性增加有关[102]。

调节性T细胞（Tregs，CD4+ CD25+ Foxp3+）在子宫中起重要作用，尤其是在围着床期，与维持子宫内膜容受性所需的抗炎环境有关[103]。不明原因RPL患者蜕膜和外周血中的Treg细胞低于对照组女性，这可能诱导母体淋巴细胞对胎儿同种异体抗原的异常活化[101-103]。研究表明，流产和不明原因RPL病例存在Treg细胞数量减少和/或功能缺陷[103-107]。Treg细胞较少与着床失败相关[89,94]，且在RPL和RIF中表现出表型改变[108-110]。因此，CD4+ CD25+ Foxp3+ T调节细胞可作为评估孕妇流产风险的优越标志物[111]。

在人类流产病例的蜕膜组织中，CD28 mRNA表达增加，而作为检查点标志物的CTLA-4 mRNA表达降低。因此，流产病例外周血和蜕膜中CTLA-4+/CD28+的比值显著低于正常妊娠[112]。

Th17细胞和Treg细胞的平衡对妊娠结局至关重要。不明原因RPL患者外周血和蜕膜中分泌IL-17、GM-CSF、IL-21和IL-22的Th17细胞水平较高[113,114]。Th17细胞升高与CD4+ CD25+ Treg细胞减少有关，这可能导致不明原因RPL[104,109-114]和RIF[115,116]。此外，可育女性的FoxP3/RORγt比值高于RIF患者[116]。

RPL合并抗甲状腺过氧化物酶抗体（anti-thyroid peroxidase，anti-TPO）阳性患者的Th17频率高于健康对照组和anti-TPO阳性对照组[117]。研究显示，RPL组的PD-1 + Th1和PD-1 + Th17细胞比例显著低于对照组，表明RPL女性Th1和Th1活性可能增加[118]。

Wang及其团队[119]综述了Th9、Th22和滤泡辅助T细胞（T follicular，Tf）等既往未被深入探讨的T细胞亚群。Th9和Th2为着床期提供耐受性环境[119]。Th22保护滋养层细胞免受感染，同时提高滋养层存活率[119]。Tf细胞有助于着床和怀孕[119]。然而，其他亚群在人类中的作用尚未被充分描述。总之，着床和蜕膜形成期间子宫内膜微环境中产生的细胞因子对受精卵的存活至关重要。需要更多研究来理解着床过程。

2.5. B细胞

关于B淋巴细胞在RPL中作用的研究较少。B细胞可能通过减少多反应性天然抗体分泌和产生保护性阻断性非对称抗体，促进妊娠成功[11]。保护性IgG母体细胞毒性抗体减少被证明与RPL有关[120,121]。此外，抗磷脂抗体与RPL和先兆子痫有关[122]。RPL女性的抗体可识别特异性子宫内膜抗原，而正常经产妇中未见此类现象[121,122]。另一方面，RPL患者子宫内膜中的B淋巴细胞（CD20+）增加[55,123]，不孕患者外周血中的CD27+ B细胞显著减少[123,124]。

B细胞与RPL相关[125]。然而，RPL女性子宫内膜和外周血中B细胞增加的机制尚不明确。子宫内膜腔中IL-10阳性B细胞数量减少与RPL有关[125,126]。尽管子宫内膜中的IL-10可能对胎儿具有保护作用，但B1和B2细胞在正常妊娠和RPL中的作用仍不清楚[125]。通常，B1细胞在组织中发挥保护作用，产生IgM抗体；而B2细胞是外周B细胞，产生IgG和IgE抗体[125]。子宫内膜腔中B细胞群的变化可能对产生对胎儿有害的抗体起到关键作用[125]。B细胞也可能通过呈递T细胞抗原引发同种异体反应。总之，尽管目前对子宫内膜腔B细胞的功能尚未阐明，但其可能是提高生育力和妊娠成功率的药理学靶点。

2.6. 髓源性抑制细胞

髓源性抑制细胞（myeloid-derived suppressor cells, MDSC）是一组具有未成熟状态和免疫抑制功能的髓源性细胞群，主要分为两种亚型：单核细胞MDSC（M-MDSC，表达CD33+HLA-DR-/低CD11b+CD14+CD15−）和多形核MDSC（PMN-MDSC，表达CD33+HLA-DR−/低CD11b+CD14−CD15+）[127]。研究表明，妊娠女性子宫及外周血MDSCs水平升高[127]。在人类中，与非孕对照组相比，健康孕妇外周循环中PMN-MDSCs显著增加[128,129]。同时，孕妇外周血中M-MDSCs升高[130]。然而，在RPL患者中观察到MDSCs在蜕膜和外周血中[128]以及孕酮反应中[131]均减少。此外，RIF患者的血液PMN-MDSCs和M-MDSCs显著降低[132]。但其他作者发现，与对照组相比，RIF或RPL患者外周血中M-MDSCs增加，且RIF患者的M-MDSCs和Tregs呈负相关[132,133,134]。目前，RPL患者的常规检测项目不包括通过流式细胞术检测MDSCs，但建议在临床分析中评估外周血免疫细胞（如调节性T细胞、Th17及NK细胞）[134]。如果可能，应在局部组织中确认这些细胞是否存在。

3. 细胞因子

白细胞介素网络失调会破坏着床过程，导致RIF[135]。TNF-α和NF-κB过表达亦对着床产生不利影响并引发RIF。在RIF患者中观察到IFN-γ/IL-4、IFN-γ/IL-10和IFN-γ/TGF-β比值升高，这与不良着床结局相关[135-137]。针对滋养层细胞的Th1型免疫反应（TNF-α、IFN-γ、IL-2）可能参与生殖衰竭，导致不明原因复发性流产；而辅助性T细胞2型（Th2、IL-4、IL-5）免疫反应可能是对滋养层细胞的自然反应，有助于成功妊娠[119,135-140]。研究表明，RPL患者外周血和蜕膜中的2型细胞因子分泌减少[141]。同样，RIF女性的Th1/Th2细胞因子比值显著高于健康女性[138,142]。

据报道，在RPL患者着床窗口期，Th17/Treg比值显著升高[143-145]。我们的研究也发现，RPL患者血清IL-17水平高于对照组[105]。此外，RIF患者子宫液体中的IL-1β水平显著高于可育对照组，而IFN-γ和IL-10的浓度显著降低[144-146]。RIF患者表现为IL-10和TGF-β分泌减少，而IL-17和IL-23分泌增加[145]。与无代谢综合征的RIF女性和对照组相比，患有代谢综合征的RIF患者IL1-β、IL-6、IL-17、TNF-α和Th17细胞频率均增加[146]。与RIF组相比，正常可育妇女的子宫内膜基质细胞和整个子宫内膜细胞产生的IL-6、IL-8和TGF-β水平更高，而子宫内膜基质细胞产生的IL-10水平较低[116,135]。

研究发现，RPL患者子宫蜕膜中的IL-22水平较低，这可能破坏蜕膜稳态并导致早期妊娠丢失[147]。同样，RPL患者蜕膜中IL-27的表达也低于对照组。IL-27抑制IL-17表达，并以剂量依赖性方式增强IL-10表达[148]。此外，IL-17和IL-27的基因多态性被发现与先兆子痫有关[149]。

Zhao等人[150]的研究发现，RPL女性患者的血清IL-33及其可溶性受体ST2浓度较高，提示这些生物标志物可用于RPL预测和治疗。此外，Yue等人[151]的研究表明，与正常妊娠早期女性相比，RPL女性的血清IL-35水平显著降低。

白血病抑制因子（Leukemia inhibitor factor，LIF）在妊娠期多种生理过程中发挥关键作用。Mrozikiewicz等人的综述研究强调，LIF水平下降与RTF有关[17]。同样，Karaer等人[152]报道，RPL女性的LIF表达发生了改变。

Raghupathy等人[153]的研究表明，相对于健康孕妇淋巴细胞中产生的IL-4和IL-10，离体暴露于黄体酮诱导的阻断因子（progesterone-induced blocking factor，PIBF）显著增加了RPL患者淋巴细胞中2型细胞因子IL-4、IL-6和IL-10的生成，但不影响1型细胞因子水平。PIBF降低了1型与2型细胞因子的比值，表明其倾向于Th2偏倚[153]。在非妊娠女性中，PIBF不影响细胞因子的产生，这凸显其在妊娠期诱导1型向2型细胞因子转变的过程。此外，Kashyap团队[154]表明，RPL女性的PIBF水平降低可能与孕激素受体亚型B的转录减少有关。这种受体下调可能不仅影响Th2/Th1细胞因子比值，还可能影响NK细胞等其他免疫细胞。该主题需要更多的研究。

通过PCR列阵数据分析发现，与对照组相比，不明原因RIF女性患者的多种细胞因子及相关因子（IL-6、IFN-γ、IL-17A、IL-23A、IFN-α1、IFN-β1、CD40 L、CCR4、CCR5、CCR6、CXR3、CCL2、IL-2、TLR4、IRF3、STAT3、RAG1、IFNAR1）表达显著上调[155]。该研究还发现，不明原因RIF组其他因子（IL-1β、IL-8、NF-kB、HLA-A、HLA-E、CD80、CD40）的表达较对照组降低[155]。研究者指出，在RIF中基于pNK细胞、Th17信号通路和TLR信号通路的炎症反应被激活[155]。值得注意的是，局部细胞因子的分泌不仅涉及基质细胞、淋巴细胞和上皮细胞，还可能受到其他调控机制的影响。此外，局部微生物群也可能调节细胞因子的分泌[26]。

4. RPL和RIF中的HLA

单倍型分析显示，RPL夫妇间MHC片段的共享水平显著高于对照家庭[156-159]。在中国人群中，DQB1 × 0604/0605等位基因可能使女性易感不明原因RPL，而DQB1 × 0501/0502等位基因可能保护女性免受RPL的影响[159]。然而，研究发现，夫妇间HLA基因位点共享（HLA-A、B、C、DR、DQ）较多（≥3个）与RIF相关[157-162]。

杀伤细胞抑制性受体（killing inhibitory receptors, KIRs）在多种病理过程发挥重要作用。当该受体与HLA配体结合时，相较于可激活细胞的短链激活型KIRs，长链抑制性KIRs会降低细胞毒性反应[163]。抑制性KIRs的配体不足，可能导致母体子宫NK细胞对滋养层细胞的抑制效应减弱，从而参与RPL的发病机制[66,163,164]。研究表明[164]，与KIR 2DL2（一种抑制性KIR）阴性女性相比，KIR 2DL2阳性的RPL白人女性及其伴侣的HLA-C1（KIR2DL2的配体）的等位基因频率较低，HLAC2（另一种KIR受体的配体）的频率较高，从而导致KIR相关的细胞杀伤抑制作用缺失[164,165]。这些研究促进了KIR遗传学及其与同种免疫生殖衰竭关系的分析。然而，目前只有一份最近的报告阐明了基因筛查的潜在好处[166]。

HLA-G是一种非经典HLA蛋白，多态性有限，主要在滋养层细胞中表达[167]。HLA-G存在多种剪接变体（包括四种膜结合亚型和3种可溶性型），在妊娠期间发挥免疫调节功能[167]。研究发现，高加索人群中HLA-G基因3′非翻译区的14碱基对插入等位基因可能会增加RIF的风险[168]。血清可溶性HLA-G（sHLA-G）水平与RIF相关[169]。携带特定单倍型的患者sHLA-G分泌水平存在差异[168]。当胚胎移植后，sHLA-G水平降低与着床失败有关[170]。

尽管目前HLA分析可能不是RIF和RPL研究的前沿，但它是一个充满未解之谜，亟待探索的迷人领域，蕴含着巨大的突破性发现潜力。

5. RPL和RIF中的免疫检查点

最近，RPL和RIF中免疫检查点蛋白的细胞表达和可溶形式引起关注[171,172]，包括PD-1/PD-L1/PDL2、OX-40/OX-40L、TIM-3、TGIT和LAG-3等[171-175]。免疫检查点的基本原理在于检查点抑制剂的表达与着床点的耐受性有关，其表达下调与细胞活化、炎症和细胞毒性有关。通过检测循环淋巴细胞中这些标志物的表达水平或评估其可溶性分子浓度，有望为评估疾病严重程度及治疗反应提供有效的生物标志物。

6. 自身免疫

自身免疫性疾病的特征在于免疫系统失调，导致针对自身抗原的体液或细胞介导性免疫反应。多种自身免疫性疾病与RPL和RIF有关，尤其是抗磷脂综合征、系统性红斑狼疮、甲状腺自身免疫和乳糜泻。此外，抗核抗体、抗甲状腺过氧化物酶抗体和抗磷脂抗体与RPL有关[176-179]。

6.1. 抗磷脂抗体（antiphospholipid antibodies，aPL）和抗磷脂综合征

抗磷脂综合征是一种以血管血栓形成（静脉/动脉）和/或妊娠并发症（妊娠丢失、胎儿死亡、因先兆子痫或胎盘功能不全导致的妊娠34周前的早产）为特征的自身免疫性疾病，与持续的抗磷脂抗体阳性相关[180]。

抗磷脂抗体[如狼疮抗凝物（LAC）和抗心磷脂（aCL）]阳性与RPL密切相关[181-185]。RPL女性中aPL患病率约为可育女性的3倍[186]。研究显示，aCL IgM女性和aPL双阳性（aCL+抗β2-糖蛋白I或/和LAC）女性更易发生胚胎丢失；而抗β2-糖蛋白I IgM阳性女性临床妊娠丢失风险更高。然而，在既往发生1-2次妊娠丢失的女性中，aPL阳性较为罕见，且与随后更高的妊娠丢失率无关[187]。

根据Papadimitriou等人[188]和Jarne-Borràs等人[189]的研究，aPL阳性与IVF着床失败率升高有关。然而，Tan XF等人[190]的荟萃分析显示，虽然aPL阳性没有降低接受IVF女性的临床妊娠率或活产率，但同时也未增加流产率。aPL可能通过抑制子宫内膜中LIF和同源框A 10的表达，影响胞饮突发育，提示aPL阳性与子宫内膜容受性受损相关，从而导致RIF[191]。

6.2. 系统性红斑狼疮和其他自身免疫性疾病

确诊患有系统性红斑狼疮（systemic lupus erythematosus，SLE）、天疱疮、硬皮病、未分化结缔组织病和类风湿性关节炎的女性面临更高的流产风险[192]。具体而言，SLE女性发生多种妊娠并发症的风险增加，包括但不限于妊娠丢失、胎儿宫内死亡、早产、胎儿宫内生长受限和胎儿先天性心脏传导阻滞[193,194]。在SLE患者中，妊娠早期补体C3、C4水平降低与流产风险增加相关。需要强调的是，妊娠丢失可能早于SLE的诊断和症状[195]。

抗核抗体（antinuclear antibodies，ANAs）可穿透细胞膜并产生细胞毒作用，可能干扰有丝分裂过程，破坏胚胎质量，从而导致RIF[196]。ANA阳性患者行IVF后发生RIF的风险增加，尤其是在年龄较大的患者中[197-200]。在未确诊自身免疫性疾病的患者中发现ANA阳性，RPL风险增加[179]。一项荟萃分析显示，与ANA阴性患者相比，ANA阳性患者的RPL风险显著增加（超过三倍）[196]。

原发性干燥综合征不仅会增加自然流产的风险[201]，还与早产、先天性心脏传导阻滞和先兆子痫有关[201,202]。

一项基于TriNetX研究网络的回顾性队列研究表明，RPL与随后确诊自身免疫性疾病风险升高有关，通常发生在RPL确诊后1-10年之间[203]。这项研究表明异常抗原呈递与RPL之间存在潜在关联。

6.3. 乳糜泻

乳糜泻患者无论营养状况如何（正常、低体重或超重），自然流产发生率均较高[204,205]。与健康人群相比，乳糜泻患者中特发性RPL发生率增加了一倍[204,205]。在一项荟萃分析中，RPL女性乳糜泻的比值比值为5.82[206]。此外，乳糜泻女性早产、宫内生长受限、死产、低出生体重和小于胎龄儿的风险显著升高[207]。

乳糜泻导致RPL的机制可能包括营养缺乏（例如锌、硒和叶酸），抗组织转谷氨酰胺酶抗体抑制滋养层细胞的侵袭能力并促进其凋亡，以及通过抑制金属蛋白酶-2激活、扰乱细胞骨架纤维的排列以及改变细胞膜的物理和机械特性来改变子宫内膜内皮细胞的分化[208,209]。

HLA-DQ2/DQ8多态性与乳糜泻相关，其在RPL患者（无乳糜泻病史）中的检出率显著高于无流产史的对照组女性（52.6% vs. 26.6%）[210]。在RPL患者中，携带HLA-DQ2/DQ8多态性患者的抗心磷脂IgG抗体及抗过氧化物酶抗体水平较不携带该多态性者更高[209]。此外，D'Ippolito等[210]发现RPL女性的ANA阳性和HLA DQ2/DQ8阳性存在统计学显著相关性，但该多态性与抗心磷脂、抗甲状腺球蛋白、抗甲状腺过氧化物酶、抗β2-糖蛋白和抗凝血酶原抗体阳性无显著关联[210,211]。

6.4. 甲状腺自身免疫

甲状腺自身免疫，即体内存在抗甲状腺过氧化物酶抗体和/或抗甲状腺球蛋白抗体（ATAs），与RIF和RPL相关。这种紊乱会导致甲状腺功能异常和免疫系统失衡[192,212]。ATAs可结合胚胎表面并干扰其发育[212]。ATAs与卵子、胚胎和胎盘抗原决定簇的交叉反应也与着床和妊娠并发症有关[212]。与无ATAs的患者相比，ATAs阳性患者的受精率、着床率和妊娠率显著降低。在RPL患者中，抗甲状腺球蛋白抗体的阳性率高于非RPL女性[213]。此外，ATAs阳性患者的流产率显著更高[214,215]。ATAs阳性可能仅是潜在自身免疫性疾病的次要标志物，而非妊娠丢失的直接原因[214,215]。与无ATAs的对照组相比，在患有自身免疫性甲状腺疾病且生育力下降的ATAs阳性女性中，观察到子宫内膜T细胞和INF-ɣ数量增加，IL-4和IL-10减少[216]。

两项随机对照试验显示，对于甲状腺功能正常但甲状腺过氧化物酶抗体阳性的女性，使用左旋甲状腺素相比安慰剂并未提高活产率[217,218]。然而，一项临床试验表明，对于甲状腺过氧化物酶抗体阳性或亚临床甲状腺功能减退症的RPL孕妇，左旋甲状腺素治疗可降低流产风险，并提高活产率[219]。在两项荟萃分析中，一项纳入了787对接受IVF/ICSI的不孕夫妇[220]，另一项纳入了15项符合条件的研究，涉及1911名参与者[221]，支持使用左旋甲状腺素治疗RPL。

为阐明这一观点，ESHRE指南将甲状腺功能减退症分为不伴自身免疫和伴自身免疫两种情况[222]。尽管左旋甲状腺素治疗亚临床甲状腺功能减退症合并RPL女性的疗效证据证据仍不明确，但对于孕前或妊娠早期确诊的甲状腺功能减退症，应使用左旋甲状腺素进行治疗。虽然亚临床甲状腺功能减退症的治疗可能会降低流产的风险，但需权衡其潜在的获益与风险。对于RPL合并亚临床甲状腺功能减退症的妊娠女性，建议在妊娠早期（7-9周）评估促甲状腺激素（thyroid-stimulating hormone，TSH）水平。若确诊甲状腺功能减退症，应启动左旋甲状腺素治疗。尽管如此，对于合并甲状腺自身免疫、RPL病史和TSH水平异常的女性，应在妊娠早期进行评估，并对确诊的甲状腺功能减退症进行左旋甲状腺素治疗。相反，甲状腺功能正常仅存在甲状腺抗体的RPL患者，不应接受左旋甲状腺素治疗。

需要更多研究来了解这些自身抗体在RIF和RPL中的重要性。

7. MicroRNAs（miRNAs）和RPL

MicroRNAs（miRNAs）影响免疫细胞的分化、增殖和功能[223]。miRNAs是短的非编码RNA（通常长度为22-24个核苷酸）通过结合mRNA的3′非翻译区，抑制mRNA翻译或诱导其降解，从而调节蛋白质的产生[223]。它们在辅助性T细胞的分化和Treg细胞的发育中发挥关键作用[223-225]。因此，在RPL和RIF中，miRNA的平衡对这两种细胞至关重要。

miRNA表达失调与RPL相关[226-228]。最近的一篇综述指出，75种miRNAs的表达在RPL女性与对照组之间的存在显著差异：53.33%上调，28%下调，18.66%在不同研究中结果不一致[227]。另一项血浆样本研究显示，与正常妊娠组相比，RPL组中77种miRNAs上调，31种miRNAs下调[228]。

在经历过流产但核型正常的女性中，miRNA-133a的表达明显上调[229]。这种过表达可能导致HLA-G蛋白表达降低，进而削弱胎儿的免疫保护，使其更容易受到免疫细胞的攻击。[229]。此外，研究还发现miR-30e、miR-34a-3p/5p、miR-141-3p/5p、miR-24、miR-486-3p、miR-6126和miR-6754-3p在RPL患者的蜕膜自然杀伤细胞和外周自然杀伤细胞中失调[230]。

特定单核苷酸多态性（single nucleotide polymorphisms，SNPs），如miR-21 rs1292037和miR-155-5p rs767649，已被发现与RPL发生率升高有关[230]。然而，目前仅有一项研究报道这些关联，其可靠性仍需更多数据验证。

在特发性RPL患者男性伴侣精子中鉴定出12个差异表达的miRNA，其中8个miRNAs上调（hsa-miR-4454、hsa-miR-142-3p、hsa-miR-145-5p、hsa-miR-1290、hsa-miR-1246、hsa-miR-7977、hsa-miR-449c-5p和hsa-miR-92b-3p），4个下调（hsa-miR-29c-3p、hsa-miR-30b-5p、hsa-miR-519a-2-5p和hsa-miR-520b-5p）[231]。

该领域相对较新，未来研究需关注细胞外囊泡的作用以及不同类型RNA在衰老和老化中的调控，这可能对胚胎着床和胎儿存活至关重要[232]。

8. RPL和RIF中的微生物群

尽管子宫内膜微生物群与早期妊娠丢失之间的因果关系尚不确定，但有一些证据表明子宫内膜微生物群可能对RPL具有预测价值[233]。RIF和RPL与女性下生殖道微生物多样性增加以及乳酸菌（Lactobacillus）优势地位丧失有关[26，233-235]。正常阴道微生物群中占主导地位的乳酸杆菌（Lactobacillus spp.）减少，与孕早期流产有关[236]。阴道微生物群中乳酸杆菌耗尽与促炎细胞因子（IL-1β、IL-6、IL-8）水平有关，相比于足月妊娠，这种关联在染色体正常的流产中更为显著[237]。

Peuranpää等人[238]的研究发现，与对照组相比，RPL女性子宫内膜样本中卷曲乳杆菌（Lactobacillus crispatus）丰度较低，而加德纳菌（Gardnerella vaginalis）在子宫内膜和阴道样本中更为富集。Vomstein等[239]观察到RPL和RIF患者在月经周期三个时间点的乳酸菌科丰度较低，在月经周期结束时变形菌门（Proteobacteria）增加[239]。值得注意的是，RIF组表现出显著多样化的微生物组成，区别于对照组和RPL组[240]。

在接受IVF的不孕症患者中，子宫内膜容受期乳酸菌属低于90%与着床率、妊娠率、持续妊娠率和活产率的显著降低有关[240]。子宫内膜样本中特定菌群（如Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus, Streptococcus, Atopobium, Bifidobacterium, and Chryseobacterium）丰度增加与流产或未妊娠有关[240]。

在RPL患者队列中，子宫内膜微生物群中脲原体属（Ureaplasma）的相对优势是正常核型后续流产的独立风险因素[241]。与终止正常妊娠的女性相比，RPL患者的变形菌门（Proteobacteria）和厚壁菌门（Firmicutes）显著升高[239,241]。此外，胚胎早期停育组阴道中拟杆菌属（Bacteroides）和幽门螺杆菌属（Helicobacter）的丰度高于正常妊娠组，乳酸杆菌丰度低于正常妊娠组。胚胎停育组中阴道惰性乳酸杆菌（Lactobacillus inners）的丰度显著低于正常妊娠组[242]。

鉴于上述有力证据，建议对拟接受不孕症和IVF治疗的患者常规进行阴道和子宫内膜微生物群筛查，同时筛查影响局部微生物群的人乳头瘤病毒。

9. RPL和RIF的免疫治疗

RIF和RPL存在多种治疗方法。表2总结了文献中提及的各类疗法。美国生殖医学学会（ASRM）和ESHRE已基于文献证据发布了相关指南，其推荐意见基于治疗手段证据强度的分级评估[222,243]。ASRM仅支持在抗磷脂综合征患者中使用肝素和阿司匹林，不推荐对其他RPL病例进行任何特定治疗。ESHRE有一些建议，将在后续内容中讨论。

表2. RIF和RPL的治疗方法

治疗	机制	效果	参考文献
皮质类固醇（治疗等级I）	降低外周NK细胞活性，增强免疫耐受；与阿司匹林联合用于自身免疫抗体阳性患者	细胞毒性功能降低。	[244,245,249]
		无抑制作用。	[246]
		提高IVF胚胎着床率。	[250,251]
		提高着床率和妊娠成功率。	[253,254]
		未增加活产率。	[255]
	联合阿司匹林/肝素用于抗磷脂综合征	提高着床率及妊娠成功率。	[256-260]
羟氯喹（治疗等级I）	抗血栓及免疫调节。	降低妊娠丢失率	[261-265]
	抗血栓及免疫调节。	剂量依赖性	[265,266]
	联合常规治疗用于抗磷脂综合征	增强Treg细胞，抑制Th17细胞。	[267]
	联合常规治疗用于抗磷脂综合征	未能预防复发性流产。	[268]
钙调磷酸酶抑制剂（治疗等级II）	环孢素和他克莫司。免疫抑制剂与出生缺陷的风险[264,265]。	提高着床率和妊娠率。	[272-275]
		治疗中出现高血压疾病	[276]
		未提高着床率	[277]
		改善着床和妊娠结局	[278-280]
	低剂量他克莫司单用或联合阿司匹林用于免疫紊乱女性。副作用小。	Th1/Th2比率减小	[281,282]
	低剂量他克莫司单用或联合阿司匹林用于免疫紊乱女性。副作用小。	子宫内膜异位症的风险-收益效应。	[283,284]
	mTOR通路在部分RIF和RPL患者中发生改变，受西罗莫司抑制[279,280]	II期临床试验，Th17/Treg突变患者。提高着床和妊娠成功率。	[285]
静脉注射免疫球蛋白（治疗等级I）	抑制HLA抗体可降低Fc受体表达并调节NK细胞。	提高妊娠成功率。高剂量更有效。	[286-296]
静脉注射免疫球蛋白（治疗等级I）	抑制HLA抗体可降低Fc受体表达并调节NK细胞。	对存在免疫问题的女性有效	[297-306,309,310]
粒细胞集落刺激因子（治疗等级II）	耐受性反应。Tregs/IL-10增加[305,306]。	提高妊娠成功率。	[313]
		与安慰剂相比无显著差异。	[314]
		对手术中的女性，皮下注射效果更好。	[315]
		皮下注射提高了RIF患者的着床成功率。	[316-319]
抗TNFα（治疗等级II）	抑制TNFα可降低局部炎症。	对自身免疫谱RPL和RIF患者有益。	[320,321]
抗TNFα（治疗等级II）	抑制TNFα可降低局部炎症。	与IVIG联用提高了妊娠成功率。	[324]
同种异体外周血单核细胞（PBMC）免疫疗法（治疗等级II）	对父亲和胎儿的HLA抗原产生耐受性反应[319-321]。	成功妊娠率增加。	[328-330,333,334,336,337]
		仅原发性RPL获益。	[331]
		无有益效果。	[334,335]
		可能引发并发症。	[19,338,339]
自体宫内（PBMC）（治疗等级II）	PBMC被人绒毛膜促性腺激素激活，产生局部耐受反应。	增加RPL患者的成功妊娠率。	[340-344]
自体宫内（PBMC）（治疗等级II）	PBMC被人绒毛膜促性腺激素激活，产生局部耐受反应。	增加子宫内膜Treg水平低患者的Tregs水平。	[345]
宫内自体富血小板血浆（治疗等级II）	局部炎症反应减少。	无显著影响。	[346]
		提高RIF患者的持续妊娠率。	[347,348]
		PRP治疗优于G-CSF输注。	[349]
脂肪乳静脉治疗（治疗等级II）	抑制NK细胞毒功能[344,345]和潜在T CD8细胞。	增加既往IVF失败患者的妊娠率。	[350,352,355]
		对妊娠率无影响。	[353,354,356]
		对子宫内膜活检中Th1高的患者有效。	[357]
		对子宫内膜NK细胞增多的患者无效。	[359]
Omega-3脂肪酸口服补充剂（治疗等级II）	减少过氧化物产生—产生消退素以减少炎症反应。	对进行常规治疗的对抗磷脂综合征RPL患者有益。	[360-362]
低分子肝素（治疗等级IV）	降低抗磷脂综合征患者的血栓风险。抗磷脂综合征患者的标准治疗[357,358]。	增加持续抗磷脂抗体阳性RPL患者的活产率。	[365,366,369-371]
		增加易栓症和RPL患者的活产率。	[367,368,379,380]
		在遗传性易栓症和异质性妊娠并发症的患者中，无显著差异。无有益效果。	[372,376-378]
低剂量阿司匹林（治疗等级IV）	抗磷脂综合征的联合治疗。	与阿司匹林单药治疗相比，LMWH联合治疗提高了活产率。	[381-386]
低剂量阿司匹林（治疗等级IV）	抗磷脂综合征的联合治疗。	单药治疗成功率较低	[387,388]
维生素D（治疗等级I）	维生素D缺乏与免疫反应受损有关。减少Th17细胞群	在RPL患者中观察到维生素D缺乏症。	[391]
维生素D（治疗等级I）	维生素D缺乏与免疫反应受损有关。减少Th17细胞群	抗磷脂综合征中维生素D减少	[324,393]
孕酮（治疗等级I）	减少炎症反应——减少巨噬细胞、NK细胞和T细胞活化[388-390]。抑制mTOR通路。	妊娠率增加（阴道给药）。	[397,399]
孕酮（治疗等级I）	减少炎症反应——减少巨噬细胞、NK细胞和T细胞活化[388-390]。抑制mTOR通路。	无效。	[398]
HCG（治疗等级II）	诱导耐受性环境	生育率增加，但活产率没有增加。	[400,401]
		效果劣于GM-CSF	[401]
		宫内GCSF给药联合hCG输注可能会改善妊娠结局	[402]
减肥药（治疗等级V）	肥胖会降低生育率。亚临床炎症可能是导致着床率和妊娠成功率降低的原因[403-405]。	二甲双胍可提高多囊卵巢综合征患者的妊娠成功率。	[406-408]

表注：治疗水平遵循Nursing-Johns Hopkins Evidence-Based Practice Model [411]。I级基于实验研究，II级基于准实验研究，III级基于非实验研究，IV级基于专家协会的意见，V级基于经验和非研究证据。

9.1. 皮质类固醇

泼尼松龙对既往流产且NK细胞数量增加的女性有益，可降低NK细胞的频率和功能[122,244,245]。然而，一项研究报道，泼尼松龙组的活产率为60%，安慰剂组为40%，但这一差异无统计学意义，可能与广泛筛查和随访有关[246]。

泼尼松龙改善了外周CD69+NK细胞水平较高的IVF患者的着床率[247]。在一项针对RPL和RIF的回顾性研究中，泼尼松龙显著降低了子宫NK细胞水平，尽管仅48.3%的患者恢复至正常水平[248]。接受泼尼松龙治疗的女性与未接受泼尼松龙治疗的女性在妊娠结局或并发症方面没有显著差异[248]。然而，一项荟萃分析表明，泼尼松龙治疗改善了RPL女性的妊娠结局[249]。同样，一项网络荟萃分析发现，阿司匹林联合糖皮质激素可改善RIF患者的流产率[250]。此外，泼尼松治疗可增加RIF患者的Treg细胞水平，并改善Th17/Treg比值[251-253]。

一项随机对照试验显示，对于抗核抗体阳性RIF患者，泼尼松（10mg/d）和阿司匹林（100mg/d）治疗可提高受精率、妊娠率和着床率，并降低流产率[254]。低剂量皮质类固醇对自身抗体（抗核抗体、抗DNA或狼疮抗凝物）阳性的RIF女性有效，显著提高妊娠率和着床率[254]。然而，在无自身免疫的RIF患者中，泼尼松治疗较安慰剂并未提高活产率，反而可能增加了早产和生化流产的风险[255]。

对于难治性抗磷脂抗体相关妊娠丢失，孕早期小剂量泼尼松龙（10mg/d）联合阿司匹林和肝素等常规治疗可能有益[256,257]。对于既往IVF失败且血清抗卵巢抗体水平显著升高的患者，泼尼松龙（0.5mg/kg）已被证明可改善妊娠率、着床率和活产率[258]。然而，必须警惕类固醇的潜在副作用，包括失眠、食欲增加、头痛、心悸、多毛症、恶心和情绪改变[246,247]。此外，使用类固醇会增加妊娠期糖尿病、先兆子痫、早产和低出生体重的风险[259,260]。

9.2. 羟氯喹

已发现羟氯喹具有抗血栓形成、抗炎和免疫调节特性[261]。研究表明，对于抗磷脂综合征（antiphospholipid syndrome, APS）和流产患者，在常规治疗中加入羟氯喹可提高活产率并减少流产率[261-265]。观察显示，羟氯喹对APS患者活产率的影响呈剂量依赖性，每日400 mg组活产率达94%，而每日200 mg组为79.5%[265]。此外，aPL抗体持续阳性患者接受羟氯喹（200-400 mg/d）治疗后不良妊娠结局减少，尤其是妊娠10周后的流产和胎盘介导的并发症（如先兆子痫、胎盘早剥和宫内生长迟缓）[266,267]。

在RIF女性中，羟氯喹可增强Tregs并降低Th17反应，但未能改善妊娠结局[268]。在最近一项非随机研究中，有RPL病史的女性在妊娠早期暴露于羟氯喹似乎并不能预防再次流产[269]。

对于具有自身免疫谱系的女性，皮质类固醇治疗仍有改进空间。

9.3. 钙调磷酸酶抑制剂

钙调磷酸酶抑制剂是一组免疫抑制剂，在阻断T细胞活化、细胞毒性、B细胞生长和抗体产生过程中特异性抑制钙/钙调磷酸酶。他克莫司和环孢素A是钙调磷酸酶抑制剂。他克莫司与FK结合蛋白-12结合，环孢素A与亲环素结合，均会产生抑制钙调磷酸酶的复合物[270]。这些药物不会增加出生缺陷风险[271]。

一项荟萃分析显示，与对照组相比，RPL或RIF患者使用钙调磷酸酶抑制剂（环孢素和他克莫司）治疗可提高活产率和临床妊娠率，并降低流产率[272,273]。低剂量环孢素A治疗（100mg或150mg/d，持续30日或6个月，妊娠试验阳性后开始）可提高RPL患者的活产率并降低流产率[274,275]。环孢素组的Th1频率、Th1/Th2比值、T-bet mRNA表达（Th1标志物）、INF-γ（Th1细胞因子）和TNF-α（Th1细胞因子）显著降低。此外，环孢素组的Th2频率、GATA结合蛋白3（Th2标志物）的mRNA表达和IL-10分泌显著增加[275]。此外，一项非随机试验显示，在对其他疗法（阿司匹林、泼尼松、肝素和父系单核细胞免疫疗法）无反应的RPL患者中，环孢素实现了77%的活产率。然而，这些患者中的相当一部分出现高血压疾病（无先兆子痫症状）和早产[276]。相反，对于未经免疫学特征筛选的RIF患者，环孢素治疗组（150 mg/d，持续2周）在着床、临床妊娠、化学妊娠、抱婴率，多胞胎率、早产、异常出生体重或性别比方面与对照组相比无显著差异[277]。

研究发现，低剂量他克莫司可改善免疫疾病和RPL女性的妊娠结局[278,279]。他克莫司在减少妊娠并发症方面疗效优于安慰剂[278-280]。此外，他克莫司可改善RIF和外周血TH1/TH2细胞比值升高女性的生育结局[281]。他克莫司联合维生素D治疗TH1/TH2细胞比值高的RPL女性，可显著提高临床妊娠率和活产率[282]。他克莫司联合低分子肝素可改善外周NK细胞升高患者的妊娠结局[281]。低剂量、短期使用环孢素和他克莫司似乎是安全的，不会导致严重的副作用，也不会增加产科和新生儿并发症的风险[281-284]。

西罗莫司，亦称雷帕霉素，是一种mTOR（雷帕霉素哺乳动物靶蛋白）抑制剂和自噬诱导剂。mTOR是一种丝氨酸/苏氨酸激酶，调节细胞代谢、增殖和分化，而自噬则参与细胞分解和再循环[285]。它在细胞应激和营养缺乏期间降解蛋白质、细胞器和细胞外侵入性物质。自噬参与子宫内膜蜕膜化和滋养层侵袭，mTOR可以抑制自噬过程[285]。西罗莫司可能通过增强子宫内膜和巨噬细胞自噬来降低流产风险。然而，这种药物可能对妊娠有害[285,286]。此外，西罗莫司可能通过逆转异常mTOR/自噬轴和调节免疫力来减少RPL和RIF的发生[285,286]。

在一项双盲II期随机临床试验中，西罗莫司治疗（2 mg/d，持续17天）提高了RIF患者的Treg细胞数量和功能，并改变了Th17/Treg比率。与对照组相比，西罗莫司治疗组的临床妊娠率（55.81% vs. 24.24%）和活产率（48.83% vs. 21.21%）显著升高[285]。因为这是一项于2019年发表的临床试验，因此还不足以确定该药物在RIF和RPL是否安全。

9.4. 静脉注射免疫球蛋白（intravenous immunoglobulins，IVIGs）

IVIGs具有多种作用机制，包括降低NK细胞活性，增加Treg细胞活性，阻断抗HLA抗体，防止补体激活，下调免疫细胞表面的刺激性Fc受体（FcγRI和FcγRIII）和上调抑制性受体（FcγRIIB）[286-289]。IVIGs可显著提高RPL的活产率，且在自身免疫的情况下，较高剂量的IVIG往往会提高妊娠成功率。然而，仍需更多高质量的随机对照试验，以在不同人群、种族、剂量和治疗时间中验证其有效性[290-294]。IVIGs以每次400 mg/kg的剂量，每3-4周给药一次，可能对伴有细胞免疫异常的RPL女性具有临床疗效[290-294]。在一项回顾性研究中，受孕前给予600-800 mg/kg的IVIGs，并在妊娠期每月给药至孕16-20周，与更高的活产率相关，尤其是在有五次或以上流产史以及原发性RPL的女性中[295]。另一项针对RPL患者的回顾性研究发现，在妊娠早期以200mg/kg的剂量每2-3周给药一次，随后每月给药至妊娠中期结束，联合低剂量阿司匹林治疗，活产率达73.5%[296]。此外，该研究发现NK细胞计数与活产率之间无显著相关性[296]。在RPL患者中，IVIG治疗组的Th1淋巴细胞频率、转录因子表达和细胞因子水平显著降低，NK细胞增加。治疗后，Th1/Th2比值显著降低，IVIG治疗组活产率为87.5%，而未治疗组为41.6%[296]。

IVIGs对免疫学特征异常的女性亚组可能更有效，在NK细胞百分比升高（>12%）和在受孕周期之前或期间干预的患者子集中，其效果更为显著。IVIGs治疗可能会提高伴潜在免疫疾病的RPL女性的活产率。然而，由于受试者数量少和非随机设计的限制，这些结果需谨慎解读[296]。

在RIF患者中，IVIGs治疗组的着床率显著高于安慰剂组。随机分配到IVIG组的患者，临床妊娠率和活产率显著提高，流产率显著降低[297-300]。在高Th1/Th2比率或低Treg/Th17比率的RIF患者中，IVIGs给药已被证明可以降低Th1/Th2比率，有效改善生殖结局[299-301]。此外，IVIGs治疗可下调RPL女性患者的Th17细胞群，上调Treg细胞群[300]。IVIGs降低了RPL或RIF患者的NK细胞水平和细胞毒性[301,302]。研究显示，在受孕前使用IVIGs，活产率显著提高，但着床后使用没有差异[303]。因此，免疫病因的RIF女性应考虑孕前使用IVIGs[303]。此外，一项荟萃分析发现，继发性RPL患者接受IVIGs治疗的活产率相对风险为1.26，而原发性RPL患者为0.88[303]。

在孕前Th1/Th2比值升高和/或NK细胞（CD56+/CD16+）增加的低生育力女性中，IVIG治疗后，IVF成功率显著高于未接受治疗者[304,305]。然而，在Th1/Th2比值正常且CD56+细胞水平正常的患者中，IVIG治疗未能提高IVF成功率[304,305]。因此，IVIGs可能对既往IVF失败且孕前Th1/Th2比值和/或NK细胞升高的患者有益[304,305]。在一项针对RPL/RIF且NK细胞水平升高患者的荟萃分析中，汇总了557名女性（312名接受干预，245名对照）的研究数据。结果显示，IVIG干预组的风险比更有利，但纳入的研究存在显著的异质性以及中至重度的偏倚风险[306]。然而，一项Cochrane评价报道，IVIGs对RPL患者的活产率并无显著影响[307]，部分研究者对此结论表示质疑[293-306]。

在一项针对不明原因RPL（≥4次）患者的双盲、随机、安慰剂对照试验中，IVIG组的活产率高于安慰剂组（58.0% vs. 34.7%）；高剂量IVIG（400 mg/kg/天，持续5天）增加了Treg细胞并降低了NK细胞活性[308]。此外，IVIGs治疗对SLE和RPL妊娠患者安全有效[302]；在有死产史的抗磷脂综合征患者中，加用低剂量阿司匹林、低分子肝素、羟氯喹和泼尼松龙，效果良好[309,310]。对于反复IVF失败且HLA基因相似（≥3个位点）的夫妇，IVIG治疗可能有益[310]。

尽管许多报告支持IVIG治疗在RIF和RPL中的应用，但仍有部分患者对治疗无反应，且确定其原因颇具挑战性。另一方面，血液制品供应减少可能会进一步影响这些复杂患者的治疗选择。

9.5. 粒细胞集落刺激因子（granulocyte colony-stimulating factor，G-CSF）

G-CSF可促进Treg细胞合成IL-10并增强移植耐受性，从而改善子宫内膜重塑和容受性[311,312]。一项随机对照试验显示，RPL女性接受皮下G-CSF治疗后，82.8%成功分娩健康婴儿，而安慰剂组为48.5%（p=0.006）[313]。然而，另一项随机对照试验发现，接受G-CSF治疗或安慰剂治疗的RPL女性，在活产率方面没有显著差异[314]。

一项荟萃分析显示，皮下注射G-CSF对RIF女性的临床妊娠率有益[315]。在RIF人群中，G-CSF给药组的临床妊娠率显著高于未干预组[316]。然而，RIF患者在胚胎移植前30分钟单剂量皮下注射G-CSF，与对照组相比，流产率、临床妊娠率或活产率均无显著差异[317]。另一项荟萃分析表明，皮下注射G-CSF比宫内注射G-CSF更有效[318]。对于子宫内膜薄或反复IVF失败的女性，与不治疗或安慰剂相比，宫内注射G-CSF后生化妊娠率和临床妊娠率显著升高[319]。总之，仍需更多临床试验以确定G-CSF在RIF和RPL中的作用。

9.6. 肿瘤坏死因子（tumor necrosis factor, TNF）-α抑制剂

TNF抑制剂可阻断TNF-α与其受体（TNFRI和TNFRII）结合，从而抑制免疫反应[15]。这些抑制剂还可降低转录因子、蛋白酶和蛋白激酶（如NF-κB、半胱天冬酶和MAPK）的活性，并减少促炎细胞因子、趋化因子和粘附分子的释放。此外，它们还抑制CD4+ T细胞向Th1和Th17细胞分化[15]。TNF-α抑制剂已被用于RPL治疗，以降低免疫排斥率。接受TNF抑制剂治疗的RPL女性妊娠结局较好。然而，目前仍缺乏足够的数据来充分支持TNF抑制剂在RPL治疗中的应用[15]。

一项针对患有先天免疫疾病的RPL患者（>3次流产）的随机对照试验报告称，从月经结束后第一天起，每周给予25毫克依那西普（一种TNF抑制剂）显著降低了TNF-α和NK细胞活性，且接受依那西普治疗的患者活产率高于安慰剂组[320]。在一项针对RIF患者的前瞻性单臂研究中，依那西普与75.9%的患者成功着床相关[314]。在另一项研究中，62%的患者实现了活产/持续妊娠；然而，56.7%的活产儿为早产儿（<37周），60.5%为体重不足（<2500g）[321]。

阿达木单抗（另一种TNF-α抑制剂）联合IVIGs显著改善了Th1/Th2细胞因子升高的年轻不孕女性的IVF结局[320,321]。相比之下，单独使用IVIG治疗无明显疗效[322,323]。抗TNF-α药（如阿达木单抗或赛妥珠单抗）已应用于难治性抗磷脂综合征，70%的患者取得了良好的产科结局[324]。此外，TNF-α阻滞剂可以在胚胎着床和妊娠期间安全使用[324]。抗TNFα可能仅适用于患有自身免疫性疾病且对治疗反应良好的RPL患者。

9.7. 同种异体外周血单核细胞（peripheral blood mononuclear cell，PBMC）免疫疗法

PBMC疗法或淋巴细胞免疫疗法（lymphocyte immunotherapy，LIT）是指从丈夫或第三方收集外周血单核细胞，并将其皮内注射（前臂或大腿）到准母亲体内，以诱导免疫系统对胚胎抗原的耐受性[319,320]。LIT的作用机制多样，包括增强抗父系细胞毒性抗体、孕酮诱导阻断因子、抗独特型抗体和混合淋巴细胞反应阻断抗体的表达，以及降低Th1/Th2比值和调节细胞因子分泌模式[325]。同种异体PBMC疗法可提高CD4+ CD25+ Treg细胞的百分比[326]，并将外周血中的Th1/Th2平衡向有利于妊娠的Th2免疫倾斜。此外，PBMC疗法显著降低了Th17和NK细胞的频率，同时增加Treg细胞频率，通过改善Treg/Th17平衡和调节相关细胞因子、转录因子和miRNA的表达，显著调节母体免疫系统。这种治疗还可以提高RPL患者的活产率[327]。

在一项前瞻性研究中，LIT改善了RPL患者的妊娠率和活产率[328]。一项回顾性分析显示，RPL合并LIT组的活产率显著高于未治疗组[329]。一项多中心观察性回顾性分析纳入了1096对有两次或两次以上自然流产史的夫妇，结果显示LIT组的妊娠成功率显著更高（60.1% vs. 33.1%; p< 0.001）[301]。在另一项针对RPL患者的研究中，LIT组的流产率显著低于仅接受孕酮治疗的对照组[330]。此外，一项研究显示，LIT对原发性RPL患者有效，但对继发性RPL患者效果不明显[331]。另一方面，在RPL患者中，父系淋巴细胞比第三方淋巴细胞更有效[332]。

REMIS研究（一项双盲多中心随机临床试验）发现，使用父系PBMC免疫接种未能改善RPL女性的妊娠结局。然而，该研究仅进行单次免疫接种，且大多数细胞通过静脉注射进行（免疫原性较弱的途径）[333]。此外，两项荟萃分析也未发现接受父系细胞免疫治疗的患者结局存在显著差异[334,335]。然而，一项荟萃分析表明，在RPL患者中，同种异体PBMC免疫治疗组的成功率显著更高。在妊娠前和妊娠期间接受治疗可显著提高RPL女性的活产率，效果优于仅在妊娠前给予PBMC免疫治疗[336]。在另一项荟萃分析中，父系细胞免疫接种与自体免疫接种的结局存在显著差异，但研究规模较小且偏倚风险较高[337]。

目前，推荐RIF患者进行LIT缺乏足够证据。必须考虑LIT潜在的并发症，如感染、自身免疫性疾病和不规则抗体[19,338,339]。

9.8. 宫内外周血单核细胞

在RIF患者中，宫内给药人绒毛膜促性腺激素激活的自体PBMC（T淋巴细胞，B淋巴细胞和单核细胞的混合物）时，着床率显著高于对照组（23.66% vs. 11.43%）[340]。在Li等的研究中也观察到了类似的结果：在四次及以上着床失败的妇女中，宫内自体PBMC组的着床、临床妊娠和活产率均显著高于对照组（分别为22.00% vs. 4.88%、39.58% vs. 14.29%和33.33% vs. 9.58%）[341]。

多项荟萃分析显示，宫内自体PBMC输注有益于临床妊娠率和活产率[14,315,342-344]。然而，一些荟萃分析显示，在新鲜/冻融胚胎移植前将PBMC注入子宫腔与RIF女性的活产率之间无显著关联[343]。

在一项回顾性研究中，子宫内膜FoxP3+ Tregs水平低的RPL女性接受了宫内Tregs输注。与未进行宫内Tregs输注的女性相比，Tregs组患者的活产率更高，流产率更低[345]。

9.9. 宫内自体富血小板血浆（platelet-rich plasma，PRP）

宫内PRP治疗可能改善RIF患者的妊娠结局。Ban Y等的回顾性研究发现，与对照组相比，PRP组的β-hCG阳性率、临床妊娠率和活产率更高[346]。一项纳入7项随机对照试验（共861例患者，存在子宫内膜薄、着床问题或妊娠失败）的荟萃分析显示，与对照组相比，接受PRP输注的女性临床妊娠率、化学妊娠率、活产率和着床率显著更高，而流产率无显著差异[346]。另外两项荟萃分析也发现，与空白组和安慰剂组相比，PRP可显著提高RIF患者的活产率[347,348]。在一项近期的临床试验中，RIF患者接受宫内PRP的效果优于宫内G-CSF[349]。

9.10. 脂肪乳静脉治疗

有证据支持在某些标准治疗失败的RPL患者中给予脂肪乳（含有大豆油、甘油和蛋黄磷脂的肠外脂肪乳剂）治疗[350]。脂肪乳治疗可有效抑制体内异常NK细胞功能，通常由4 mL 20%浓度的脂肪乳与250 mL生理盐水混合组成。其对NK细胞功能和数量的影响长达6周[351]。在一项单盲随机对照试验中，与对照组相比，接受脂肪乳治疗的既往IVF失败患者的生化妊娠率（40.38% vs. 16%）和抱婴率（28.8% vs. 10%）的显著更高[352]。此外，一项双盲随机对照试验表明，对于不明原因RPL和NK细胞活性阳性的IVF/ICSI周期女性，脂肪乳给药可提高持续妊娠率和活产率[352]。然而，另一项研究发现，脂肪乳给药虽会增加化学妊娠率和临床妊娠率，降低自然流产率，但这些差异均无统计学意义[353]。

一项荟萃分析纳入了5项随机对照试验（3项：RIF女性，1项：RPL女性，1项：经历着床失败不只一次的女性）涉及840例患者，结果显示，与对照组相比，脂肪乳给药显著提高了临床妊娠率、持续妊娠率和活产率，但对流产率无显著影响[354]。另一项纳入12项研究的荟萃分析表明，脂肪乳可改善RPL/RIF患者的着床率、妊娠率和活产率，并降低流产率[354]。Rimmer等的荟萃分析评估了843例RIF女性患者，纳入了5项具有中等偏倚风险的随机试验，发现与无干预组相比，脂肪乳组的临床妊娠和活产几率更高[355]。在最近一项随机对照试验的荟萃分析中，与对照组相比，脂肪乳提高了RPL/RIF女性的临床妊娠率、持续妊娠率和活产率，但流产率无显著差异[356]。此外，脂肪乳治疗对子宫内膜活检中Th1细胞升高的RIF和RPL患者有效[357]。然而，一项包含历史对照的回顾性研究显示，对于NK细胞升高的RPL或RIF患者，脂肪乳治疗未能改善的活产率且成本效益不高[358]。因此，脂肪乳治疗可能仅对特定的患者亚组有效[359]。

9.11. Omega 3脂肪酸补充剂

补充omega-3脂肪酸已被成功用于患有抗磷脂综合征的RPL患者[360]。正如Mu及其同事[361]在最近一篇综述中所述，使用omega-3脂肪酸的基本原理是减少自由基的形成，减少促炎脂质产物，同时增加消退素，进而调节免疫细胞产生耐受反应。此外，omega-3脂肪酸可调节肠道微生物群及其代谢物的生成，进而降低RPL患者中常见的全身性促炎反应[26]。Canela及其同事发现RIF和RPL患者接受含10%鱼油的脂肪乳治疗后，磷脂成分发生显著变化[362]。这些变化有望作为生物标志物。需要更多的临床试验来确定omega-3脂肪酸治疗在RPL和RIF中的重要性。

9.12. 低分子肝素（low-molecular-weight heparin，LMWH）

国际专业指南推荐使用肝素治疗抗磷脂综合征[363,364]。与单用阿司匹林治疗相比，妊娠期联合使用肝素和阿司匹林可能会提高存在持续性抗磷脂抗体的RPL女性的活产率[365,366]。

一些研究发现，LMWH与易栓症和妊娠丢失女性的活产机会增加有关[367,368]。一项针对RPL且抗磷脂抗体阴性女性的随机研究显示，LMWH组的抱婴率显著高于对照组[369]。一篇纳入8项随机对照试验的荟萃分析也显示，与对照组相比，LMWH可显著提高RPL患者的活产率并降低流产率[370]。同样，一项纳入RPL患者的荟萃分析显示，LMWH联合阿司匹林组的活产率显著高于单用阿司匹林组[371]。然而，一项荟萃分析发现，对于遗传性易栓症和多种妊娠并发症的患者，妊娠期使用LMWH与否，活产率并无显著差异[372]。同样，一项荟萃分析证明肝素、阿司匹林或两者联用对RPL患者的活产率无益[373]，另一项随机对照试验显示，每日注射LMWH并未增加不明原因RPL女性的持续妊娠率或活产率[374]。在RPL和因子V. Leiden突变的患者中，单用低剂量阿司匹林、LMWH联合阿司匹林或单用LMWH的活产率相当[375]。

一项纳入3项小型随机对照试验的荟萃分析显示，RPL患者接受肝素治疗与否，在活产率、流产率、胎龄或出生体重方面无显著差异[376]。另一项涉及不明原因RPL女性的荟萃分析（5项研究，1452名参与者）发现，LMWH降低了既往流产≥3次女性的流产风险，但对活产率、早产、先兆子痫或小于胎龄儿无实质性影响[377]。最近的一项荟萃分析（RPL患者，LMWH联合或不联合低剂量阿司匹林）也未显示对活产率有益[378]。相比之下，一项回顾性分析发现，肝素治疗可降低不明原因RPL患者和抗磷脂综合征或易栓症患者的流产率[379]。

ALIFE2试验是一项前瞻性随机研究，纳入了326例遗传性易栓症和RPL患者，发现LMWH组患者与对照组的活产率无显著差异（72% vs 71%）[380]。因此，有必要分析这些研究结果差异的原因。

9.13. 低剂量阿司匹林

低剂量阿司匹林和肝素适用于抗磷脂综合征[381]。在RPL合并抗磷脂综合征患者中，单用阿司匹林的活产率低于LMWH联合阿司匹林[381]。在OPTIMUM治疗策略中，对于存在易栓症的RPL/RIF患者（狼疮抗凝物、抗心磷脂抗体、抗β2-GP1抗体水平、蛋白C、蛋白S活性以及因子XII水平改变）接受81 mg/d的阿司匹林治疗，不使用肝素[279,382-384]。在RPL患者中，单用低剂量阿司匹林组的活产率为77.1%，而LMWH组的活产率为78%[384]。

在一项针对无易栓症的RPL患者的随机研究中，低剂量阿司匹林（100 mg/d）组与依诺肝素（40 mg/d）组的活产率相当。在原发性RPL（无活产史）患者中，依诺肝素治疗组的活产率为94%，而阿司匹林治疗组为81%[385]。Nami及其同事报道在既往有1-2次流产的患者中，与安慰剂相比，阿司匹林可显著提高妊娠率（由人绒毛膜促性腺激素检测）、降低流产率，并增加活产率[386]。

然而，Mumford等人报道，在有1-2次流产史的女性中，孕前给予低剂量阿司匹林与安慰剂相比，流产率无显著差异[387]。此外，阿司匹林未能预防妊娠早期连续三次及以上流产妇女的复发性流产。在该试验中，阿司匹林组和安慰剂组的活产率均较高（分别为83.0%和85.5%）[388]。

对于可能存在亚临床自身免疫或易栓症倾向的RPL和RIF患者，不应考虑采用阿司匹林单药治疗。

9.14. 维生素D

一项体外研究表明，维生素D疗法可通过抑制细胞毒性Th1细胞增殖、促进Th2细胞生成、抑制Th17细胞和诱导Treg细胞，来调节辅助性T细胞群[389]。此外，维生素D对NK细胞的细胞毒性、细胞因子分泌及脱颗粒过程具有免疫调节作用[390]。

维生素D缺乏及不足与流产有关[391]，64.6%的RPL患者存在维生素D不足或缺乏[392]。推荐产科抗磷脂综合征患者补充维生素D[324]。然而，一项荟萃分析指出，目前尚不清楚孕前治疗维生素D缺乏症，能否预防有流产风险的女性的流产[393]。在RPL患者中，与维生素D水平正常的患者相比，维生素D水平较低患者的aPL抗体、ANA、抗ssDNA和甲状腺过氧化物酶抗体的患病率显著升高[393]。

鉴于维生素D已被证实具有调节免疫细胞反应的作用，其缺乏与RPL和RIF有关不足为奇。未来需要更多设计良好的试验关注维生素D缺乏的问题。

9.15. 孕酮

孕酮是一种免疫抑制激素，可在滋养层侵袭过程中调节NK细胞活性和细胞因子平衡，并促进CD56bright群体的增加。孕酮诱导阻断因子由表达孕酮受体的淋巴细胞和滋养层细胞分泌，促使免疫应答向Th2型转变[394]。孕酮可有效抑制Th1和Th17细胞产生的mTOR通路，并诱导Treg细胞分化[394-396]。一项Cochrane荟萃分析显示，孕酮有助于降低女性复发性流产风险[397]。另一项荟萃分析表明，虽然孕酮或类似分子几乎不影响先兆或复发性流产妇女的活产率，但阴道微粉化孕酮可能增加有流产史和孕早期出血女性的活产率[398]。最近一项针对妊娠丢失风险增加女性的荟萃分析也显示，使用孕酮可能会提高其活产率。对于先兆流产患者，如果有流产史，这种治疗效果更好[399]。在RPL患者的黄体期给药时，成功率更高[338]。

尽管孕酮已在临床应用多年，但仍需通过设计严谨的临床试验来明确最佳药物联用方案，以提升生育率及妊娠成功率。

9.16. 宫内人绒毛膜促性腺激素（human chorionic gonadotropin，hCG）输注

一项荟萃分析显示，宫内hCG输注组的临床妊娠率显著优于空白组和安慰剂组[400]。另一项荟萃分析显示，在经历2次或以上着床失败的女性中，hCG组的临床妊娠率和活产率显著优于对照组[401]。在一项前瞻性双盲随机临床试验中，宫内GCSF给药联合hCG输注对妊娠率有轻微但不显著的改善作用[402]。

hCG的使用仍处于初步阶段，可能需要通过多种替代方法来验证其效果。

9.17. 减肥药

近年来，超重和肥胖发病率升高可能对生育率产生显著影响。肥胖已被证实会损害子宫内膜容受性，改变着床窗口期[403,404]。据推测，肥胖与亚临床炎症（代谢综合征的表现）的关联，可能是肥胖女性着床失败率和复发性流产率较高的原因[405]。鉴于胰岛素抵抗等代谢变化与一系列免疫和内分泌反应有关，减肥和胰岛素抵抗治疗可能有助于提高生育率，降低复发性流产率。

二甲双胍已被用于治疗多囊卵巢综合征，这些患者RIF和RPL发生率较高[406]。该药物还用于妊娠期糖尿病治疗，且可能改善肥胖女性的其他妊娠并发症[407,408]。据推测，除了降低胰岛素抵抗外，二甲双胍还调节免疫反应，这可能会影响脂肪组织反应和脂肪因子的分泌和功能。

最近，胰高血糖素样肽-1受体激动剂（GLP-1a）已被用于治疗糖尿病和肥胖症[409]。减少脂肪组织可能会提高生育力[409,410]。然而，需要精心设计的临床试验，来确定计划怀孕或IVF手术前治疗的有效性。

上述疗法相关的ESHRE指南如下：

1) 不推荐将糖皮质激素用于治疗不明原因RPL或存在特定免疫学生物标志物的RPL患者。现有证据不足以支持在伴有黄体功能不全的RPL患者中使用孕酮提高活产率。但针对三次及以上流产史且本次妊娠阴道出血者，阴道孕酮可能对改善活产率具有积极作用。

2) 对于无抗磷脂综合征的RPL患者，不建议使用肝素或低剂量阿司匹林。现有证据表明，这些干预措施无法提高不明原因RPL女性的活产率。

3) hCG改善黄体功能不全型RPL患者活产率有效性的证据不充分。此外，在合并糖代谢异常的RPL患者中，妊娠期补充二甲双胍预防流产证据不足。

4) RPL女性孕前预防性补充维生素D可能是有益的。应在孕前开始补充低剂量叶酸，以预防神经管缺陷，但其对不明原因RPL的流产预防作用尚未证实。鉴于证据不足，当前指南不推荐将维生素补充剂作为治疗手段。应适当告知患者补充维生素的潜在危害，特别是维生素E、A。

5) 没有证据支持在不明原因RPL中使用G-CSF。

6) 鉴于疗效不显著和存在潜在严重不良反应，不建议使用淋巴细胞免疫疗法治疗不明原因RPL。然而，对于经历4次及以上不明原因RPL的女性，怀孕早期重复给予高剂量IVIGs可能会提高活产率。

7) 缺乏足够证据支持脂肪乳治疗用于提高不明原因RPL患者的活产率。

8) 根据欧洲人类生殖与胚胎学学会声明，关于针对RPL夫妇的替代疗法（包括顺势疗法、生物共振疗法和NaPro技术）的研究较少。

10. 展望

越来越有必要全面理解与RIF和RPL相关的生理和病理过程，包括原发性和继发性。生殖医学的最新进展，特别是关于脂肪组织反应和脂肪因子的调节，可能在识别这些患者方面发挥关键作用。此外，宫内膜异位症和子宫内膜炎可能是RIF和RPL的重要因素。实施减少子宫内膜内炎症的新策略有望丰富现有治疗选择。此外，多样的治疗方法也导致对结果的解释具有复杂性和挑战性。

此外，亟待制定相关指南来指导无明确自身免疫性疾病谱患者的分析和治疗。针对已知自身免疫性疾病的患者已取得一定进展，完善的免疫学筛查和个体化免疫调节疗法可能对RIF和RPL有潜在益处。

由于菌群失调与胚胎着床和胎儿存活率降低有关，应对就诊于生殖门诊的患者常规进行微生物群分析。此外，病原体的分子模拟在自身免疫谱的发展中发挥重要作用。

11. 结论

NK细胞、Treg细胞、Th2和细胞因子异常在RPL和RIF中发挥关键免疫调控作用。通过纠正NK细胞紊乱、抑制Th17和Th1细胞模式以及促进Treg和Th2淋巴细胞，可能有助于提高活产率。

RPL和RIF的病因呈现多样性和复杂性，患者具有异质性，涉及多种免疫和非免疫因素。应结合患者的免疫学和内分泌学因素设计治疗方案以实现积极的治疗效果。总之，应考虑个体化治疗。

鉴于传染病和微生物群失调的发生率不断增加，建议开展相关医学筛查。

参考文献

1.Tomkiewicz, J.; Darmochwał-Kolarz, D. The Diagnostics and Treatment of Recurrent Pregnancy Loss. J. Clin. Med. 2023, 12, 4768.

2.The ESHRE Guideline Group on RPL; Bender Atik, R.; Christiansen, O.B.; Elson, J.; Kolte, A.M.; Lewis, S.; Middeldorp, S.; Nelen, W.; Peramo, B.; Quenby, S.; et al. ESHRE guideline: Recurrent pregnancy loss. Hum. Reprod. Open 2018, 2018, hoy004.

3.Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: A committee opinion. Fertil. Steril. 2012, 98, 1103–1111.

4.Who: Recommended Definitions, Terminology, and Format for Statistical Tables Related to The Perinatal Period And Use of A New Certificate For the Cause of Perinatal Deaths. Acta Obstet. Gynecol. Scand. 1977, 56, 247–256.

5.Dimitriadis, E.; Menkhorst, E.; Saito, S.; Kutteh, W.H.; Brosens, J.J. Recurrent pregnancy loss. Nat. Rev. Dis. Primers 2020, 6, 98.

6.Dong, P.; Wen, X.Z.; Liu, J.; Yan, C.; Yuan, J.; Luo, L.; Hu, Q.F.; Li, J. Simultaneous detection of decidual Th1/Th2 and NK1/NK2 immunophenotyping in unknown recurrent miscarriage using 8-color flow cytometry with FSC/Vt extended strategy. Biosci. Rep. 2017, 37, BSR20170150.

7.Kohl Schwartz, A.S.; Wölfler, M.M.; Mitter, V.; Rauchfuss, M.; Haeberlin, F.; Eberhard, M.; von Orelli, S.; Imthurn, B.; Imesch, P.; Fink, D.; et al. Endometriosis, especially mild disease: A risk factor for miscarriages. Fertil. Steril. 2017, 108, 806–814.e2.

8.Harb, H.M.; Ghosh, J.; Al-Rshoud, F.; Karunakaran, B.; Gallos, I.D.; Coomarasamy, A. Hydrosalpinx and pregnancy loss: A systematic review and meta-analysis. Reprod. Biomed. Online 2019, 38, 427–441.

9.Zhang, L.; Li, H.; Han, L.; Zhang, L.; Zu, Z.; Zhang, J. Association between semen parameters and recurrent pregnancy loss: An umbrella review of meta-analyses. J. Obstet. Gynaecol. Res. 2024, 50, 545–556.

10.Deshmukh, H.; Way, S.S. Immunological Basis for Recurrent Fetal Loss and Pregnancy Complications. Annu. Rev. Pathol. 2019, 14, 185–210.

11.Bagkou Dimakou, D.; Lissauer, D.; Tamblyn, J.; Coomarasamy, A.; Richter, A. Understanding human immunity in idiopathic recurrent pregnancy loss. Eur. J. Obstet. Gynecol. Reprod. Biol. 2022, 270, 17–29.

12.Bashiri, A.; Halper, K.I.; Orvieto, R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions. Reprod. Biol. Endocrinol. 2018, 16, 121.

13.Comins Boo, A.; Segovia, A.G.; del Prado, N.N.; de la Fuente, L.; Alonso, J.; Ramon, S.S. Evidence-based Update: Immunological Evaluation of Recurrent Implantation Failure. Reprod. Immunol. Open Access. 2016, 1, 24.

14.Wu, Y.; Li, L.; Liu, L.; Yang, X.; Yan, P.; Yang, K.; Zhang, X. Autologous peripheral blood mononuclear cells intrauterine instillation to improve pregnancy outcomes after recurrent implantation failure: A systematic review and meta-analysis. Arch. Gynecol. Obstet. 2019, 300, 1445–1459.

15.Wu, H.; You, Q.; Jiang, Y.; Mu, F. Tumor necrosis factor inhibitors as therapeutic agents for recurrent spontaneous abortion. Mol. Med. Rep. 2021, 24, 847.

16.Saadaoui, M.; Singh, P.; Ortashi, O.; Al Khodor, S. Role of the vaginal microbiome in miscarriage: Exploring the relationship. Front. Cell. Infect. Microbiol. 2023, 13, 1232825.

17.Mrozikiewicz, A.E.; Ozarowski, M.; J˛edrzejczak, P. Biomolecular Markers of Recurrent Implantation Failure—A Review. ˙ Int. J. Mol. Sci. 2021, 22, 10082.

18.Wang, Q.; Sun, Y.; Fan, R.; Wang, M.; Ren, C.; Jiang, A.; Yang, T. Role of inflammatory factors in the etiology and treatment of recurrent implantation failure. Reprod. Biol. 2022, 22, 100698.

19.Ma, J.; Gao, W.; Li, D. Recurrent implantation failure: A comprehensive summary from etiology to treatment. Front. Endocrinol. 2023, 13, 1061766.

20.Fathi, M.; Omrani, M.A.; Kadkhoda, S.; Ghahghaei-Nezamabadi, A.; Ghafouri-Fard, S. Impact of miRNAs in the pathoetiology of recurrent implantation failure. Mol. Cell Probes 2024, 74, 101955.

21.Liu, L.; Liu, Y.; Tian, Y.; Cao, Y.; Wang, T.; Mi, S.; Yang, R.; Liu, S.; Ma, X.; Wang, J. Identification of Differentially Expressed mRNAs and lncRNAs Contributes to Elucidation of Underlying Pathogenesis and Therapeutic Strategy of Recurrent Implantation Failure. Reprod. Sci. 2024.

22.Zahir, M.; Tavakoli, B.; Zaki-Dizaji, M.; Hantoushzadeh, S.; Majidi Zolbin, M. Non-coding RNAs in Recurrent implantation failure. Clin. Chim. Acta 2024, 553, 117731.

23.Colamatteo, A.; Fusco, C.; Micillo, T.; D’Hooghe, T.; de Candia, P.; Alviggi, C.; Longobardi, S.; Matarese, G. Immunobiology of pregnancy: From basic science to translational medicine. Trends Mol. Med. 2023, 29, 711–725.

24.Zhao, F.; Hu, X.; Ying, C. Advances in Research on the Relationship between Vaginal Microbiota and Adverse Pregnancy Outcomes and Gynecological Diseases. Microorganisms. 2023, 11, 991.

25.Moreno, I.; Codoñer, F.M.; Vilella, F.; Valbuena, D.; Martinez-Blanch, J.F.; Jimenez-Almazán, J.; Alonso, R.; Alamá, P.; Remohí, J.; Pellicer, A.; et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am. J. Obstet. Gynecol. 2016, 215, 684–703.

26.Garmendia, J.V.; De Sanctis, C.V.; Hajdúch, M.; De Sanctis, J.B. Microbiota and Recurrent Pregnancy Loss (RPL); More than a Simple Connection. Microorganisms. 2024, 12, 1641.

27.Jia, D.; Sun, F.; Han, S.; Lu, L.; Sun, Y.; Song, Q. Adverse outcomes in subsequent pregnancies in women with a history of recurrent spontaneous abortion: A meta-analysis. J. Obstet. Gynaecol. Res. 2024, 50, 281–297.

28.Field, K.; Murphy, D.J. Perinatal outcomes in a subsequent pregnancy among women who have experienced recurrent miscarriage: A retrospective cohort study. Hum. Reprod. 2015, 30, 1239–1245.

29.Fang, Y.; Jingjing, F.; Tiantain, C.; Huanhuan, X.; Qiaohua, H. Impact of the number of previous embryo implantation failures on IVF/ICSI-ET pregnancy outcomes in patients younger than 40 years: A retrospective cohort study. Front. Endocrinol. 2023, 14, 1243402.

30.Cimadomo, D.; Rienzi, L.; Conforti, A.; Forman, E.; Canosa, S.; Innocenti, F.; Poli, M.; Hynes, J.; Gemmell, L.; Vaiarelli, A.; et al. Opening the black box: Why do euploid blastocysts fail to implant? A systematic review and meta-analysis. Hum. Reprod. Update 2023, 29, 570–633.

31.Nitu, R.; Neamtu, R.; Lordache, O.; Stelea, L.; Dahma, G.; Sacarin, G.; Socol, G.; Boarta, A.; Silaghi, C.; Puichita, D.; et al. Cross-Sectional Analysis of Intimacy Problems, Stress Levels, and Couple Satisfaction among Women with Thrombophilia Affected by Recurrent Pregnancy Loss. Int J Environ Res Public Health. 2023, 20, 1208.

32.Chen, S.; Chang, S.; Kuo, P.; Chen, C. Stress, anxiety and depression perceived by couples with recurrent miscarriage. Int J Nurs Pract. 2020, 26, e12796.

33.Quenby, S.; Gallos, I.D.; Dhillon-Smith, R.K.; Podesek, M.; Stephenson, M.D.; Fisher, J.; Brosens, J.J.; Brewin, J.; Ramhorst, R.; Lucas, E.S.; et al. Miscarriage matters: The epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021, 397, 1658–1667.

34.Voss, P.; Schick, M.; Langer, L.; Ainsworth, A.; Ditzen, B.; Strowitzki, T.; Wischmann, T.; Kuon, R.J. Recurrent pregnancy loss: A shared stressor---couple-orientated psychological research findings. Fertil Steril. 2020, 114, 1288–1296.

35.Mínguez-Alarcón, L.; Williams, P.L.; Souter, I.; Ford, J.B.; Hauser, R.; Chavarro, J.E. Women’s preconception psychological stress and birth outcomes in a fertility clinic: The EARTH study. Front Glob Womens Health. 2024, 5, 1293255.

36.Marshall, J.S.; Warrington, R.; Watson, W.; Kim, H.L. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2018, 14 (Suppl. 2), 49.

37.Garmendia, J.V.; De Sanctis, J.B. A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation. Immuno. 2021, 1, 174–193.

38.Lanier, L.L. Five decades of natural killer cell discovery. J. Exp. Med. 2024, 221, e20231222.

39.Rao, V.A.; Kurian, N.K.; Rao, K.A. Cytokines, NK cells, and regulatory T cell functions in normal pregnancy and reproductive failures. Am. J. Reprod. Immunol. 2023, 89, e13667.

40.Cavalcante, M.B.; da Silva, P.H.A.; Carvalho, T.R.; Sampaio, O.G.M.; Câmara, F.E.A.; Cavalcante, C.T.M.B.; Barini, R.; Kwak-Kim, J. Peripheral blood natural killer cell cytotoxicity in recurrent miscarriage: A systematic review and meta-analysis. J. Reprod. Immunol. 2023, 158, 103956.

41.Sacks, G.; Yang, Y.; Gowen, E.; Smith, S.; Fay, L.; Chapman, M. Detailed Analysis of Peripheral Blood Natural Killer Cells in Women with Repeated IVF Failure. Am. J. Reprod. Immunol. 2012, 67, 434–442.

42.Cai J.Y., Tang Y.Y., Deng X.H., Li Y.J., Liang G., Meng Y.Q., Zhou H. Recurrent Implantation Failure May Be Identified by a Combination of Diagnostic Biomarkers: An Analysis of Peripheral Blood Lymphocyte Subsets. Front. Endocrinol. 2024;13:865807.

43.Sacks G. Enough! Stop the arguments and get on with the science of natural killer cell testing. Hum. Reprod. 2015;30:1526–1531. doi: 10.1093/humrep/dev096.

44.Dons’koi B.V. Accentuated hypo- and hyper-NK lymphocyte CD8 expression is a marker of NK subsets’ misbalance and is predictive for reproductive failures. Immunobiology. 2015;220:649–655.

45.Dons’koi B.V., Chernyshov V.P., Sirenko V.Y., Strelko G.V., Osypchuk D.V. Peripheral blood natural killer cells activation status determined by CD69 upregulation predicts implantation outcome in IVF. Immunobiology. 2014;219:167–171.

46.Gothe J.P., de Mattos A.C., Silveira C.F., Malavazi K.C. Exploring Natural Killer Cell Testing in Embryo Implantation and Reproductive Failure: An Overview of Techniques and Controversies. Reprod. Sci. 2024;31:603–632.

47.Zhang J., Lye S.J. The immune potential of decidua-resident CD16+CD56+ NK cells in human pregnancy. Hum. Immunol. 2021;82:332–339. doi: 10.1016/j.humimm.2021.01.014.

48.Salazar M.D., Wang W.J., Skariah A., He Q., Field K., Nixon M., Reed R., Dambaeva S., Beaman K., Gilman-Sachs A., et al. Post-hoc evaluation of peripheral blood natural killer cell cytotoxicity in predicting the risk of recurrent pregnancy losses and repeated implantation failures. J. Reprod. Immunol. 2022;150:103487. doi: 10.1016/j.jri.2022.103487. [DOI] [PubMed] [Google Scholar]

49.Singh N., Dogra Y., Kumar P., Mathur S., Sharma A., Patel G. Establishment of Cut-off Values for Uterine and Peripheral Blood Natural Killer Cells During the Peri-implantation Period in Fertile Controls and Women with Unexplained Recurrent Implantation Failure. J. Reprod. Infert. 2023;24:248–256. doi: 10.18502/jri.v24i4.14152. [DOI] [PMC free article] [PubMed] [Google Scholar]

50.Santillán I., Fernández Lozano I., Illán J., Verdú V., Coca S., Bajo-Arenas J., Martinez F. Where and when should natural killer cells be tested in women with repeated implantation failure? J. Reprod. Immunol. 2015;108:142–148. doi: 10.1016/j.jri.2014.12.009. [DOI] [PubMed] [Google Scholar]

51.Sfakianoudis K., Rapani A., Grigoriadis S., Pantou A., Maziotis E., Kokkini G., Tsirligkani C., Bolaris S., Nikolettos K., Chronopoulou M., et al. The Role of Uterine Natural Killer Cells on Recurrent Miscarriage and Recurrent Implantation Failure: From Pathophysiology to Treatment. Biomedicines. 2021;9:1425. doi: 10.3390/biomedicines9101425. [DOI] [PMC free article] [PubMed] [Google Scholar]

52.Bagkou Dimakou D., Tamblyn J., Justin C., Coomarasamy A., Richter A. Diagnosis and management of idiopathic recurrent pregnancy loss (RPL): Current immune testing and immunomodulatory treatment practice in the United Kingdom. J. Reprod. Immunol. 2022;153:103662. doi: 10.1016/j.jri.2022.103662. [DOI] [PubMed] [Google Scholar]

53.Seshadri S., Sunkara S.K. Natural killer cells in female infertility and recurrent miscarriage: A systematic review and meta-analysis. Hum. Reprod. Update. 2013;20:429–438. doi: 10.1093/humupd/dmt056. [DOI] [PubMed] [Google Scholar]

54.Lachapelle M., Miron P., Hemmings R., Roy D. Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion. Altered profile and pregnancy outcome. J. Immunol. 1996;156:4027–4034. doi: 10.4049/jimmunol.156.10.4027. [DOI] [PubMed] [Google Scholar]

55.Ho Y.K., Chen H.H., Huang C.C., Lee C.I., Lin P.Y., Lee M.S., Lee T.H. Peripheral CD56+CD16+ NK Cell Populations in the Early Follicular Phase Are Associated With Successful Clinical Outcomes of Intravenous Immunoglobulin Treatment in Women With Repeated Implantation Failure. Front. Endocrinol. 2020;10:937. doi: 10.3389/fendo.2019.00937. [DOI] [PMC free article] [PubMed] [Google Scholar]

56.Fukui A., Fujii S., Yamaguchi E., Kimura H., Sato S., Saito Y. Natural Killer Cell Subpopulations and Cytotoxicity for Infertile Patients Undergoing In Vitro Fertilization. Am. J. Reprod. Immunol. 1999;41:413–422. doi: 10.1111/j.1600-0897.1999.tb00456.x. [DOI] [PubMed] [Google Scholar]

57.Strobel L., Vomstein K., Kyvelidou C., Hofer-Tollinger S., Feil K., Kuon R.J., Ebner S., Troppmair J., Toth B. Different Background: Natural Killer Cell Profiles in Secondary versus Primary Recurrent Pregnancy Loss. J. Clin. Med. 2021;10:194. doi: 10.3390/jcm10020194. [DOI] [PMC free article] [PubMed] [Google Scholar]

58.Fukui A., Kwak-Kim J., Ntrivalas E., Gilman-Sachs A., Lee S.K., Beaman K. Intracellular cytokine expression of peripheral blood natural killer cell subsets in women with recurrent spontaneous abortions and implantation failures. Fertil. Steril. 2008;89:157–165. doi: 10.1016/j.fertnstert.2007.02.012. [DOI] [PubMed] [Google Scholar]

59.Díaz-Peña R., de Los Santos M.J., Lucia A., Castro-Santos P. Understanding the role of killer cell immunoglobulin-like receptors in pregnancy complications. J. Assist. Reprod. Genet. 2019;36:827–835. doi: 10.1007/s10815-019-01426-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

60.Lin Q.D., Qiu L.H. Pathogenesis, diagnosis, and treatment of recurrent spontaneous abortion with immune type. Front. Med. China. 2010;4:275–279. doi: 10.1007/s11684-010-0101-y. [DOI] [PubMed] [Google Scholar]

61.Dambaeva S.V., Lee D.H., Sung N., Chen C.Y., Bao S., Gilman-Sachs A., Kwak-Kim J., Beaman K.D. Recurrent Pregnancy Loss in Women with Killer Cell Immunoglobulin-Like Receptor KIR2DS1 is Associated with an Increased HLA-C2 Allelic Frequency. Am. J. Reprod. Immunol. 2016;75:94–103. doi: 10.1111/aji.12453. [DOI] [PubMed] [Google Scholar]

62.Akbari S., Shahsavar F., Karami R., Yari F., Anbari K., Ahmadi S.A.Y. Recurrent Spontaneous Abortion (RPL) and Maternal KIR Genes: A Comprehensive Meta-Analysis. JBRA Assist. Reprod. 2020;24:197–213. doi: 10.5935/1518-0557.20190067. [DOI] [PMC free article] [PubMed] [Google Scholar]

63.Yang X., Yang E., Wang W., He Q., Jubiz G., Katukurundage D., Dambaeva S., Beaman K.D., Kwak-Kim J. Decreased HLA-C1 alleles in couples of KIR2DL2 positive women with recurrent pregnancy loss. J. Reprod. Immunol. 2020;142:103186. doi: 10.1016/j.jri.2020.103186. [DOI] [PubMed] [Google Scholar]

64.Feyaerts D., Benner M., Comitini G., Shadmanfar W., van der Heijden O.W.H., Joosten I., van der Molen R.G. NK cell receptor profiling of endometrial and decidual NK cells reveals pregnancy-induced adaptations. Front. Immunol. 2024;15:1353556. doi: 10.3389/fimmu.2024.1353556. [DOI] [PMC free article] [PubMed] [Google Scholar]

65.Maftei R., Doroftei B., Popa R., Harabor V., Adam A.M., Popa C., Harabor A., Adam G., Nechita A., Vasilache I.A., et al. The Influence of Maternal KIR Haplotype on the Reproductive Outcomes after Single Embryo Transfer in IVF Cycles in Patients with Recurrent Pregnancy Loss and Implantation Failure—A Single Center Experience. J. Clin. Med. 2023;12:1905. doi: 10.3390/jcm12051905. [DOI] [PMC free article] [PubMed] [Google Scholar]

66.Nowak I., Wilczyńska K., Wilczyński J.R., Malinowski A., Radwan P., Radwan M., Kuśnierczyk P. KIR, LILRB and their Ligands’ Genes as Potential Biomarkers in Recurrent Implantation Failure. Arch. Immunol. Ther. Exp. 2017;65:391–399. doi: 10.1007/s00005-017-0474-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

67.Braun A.S., Vomstein K., Reiser E., Tollinger S., Kyvelidou C., Feil K., Toth B. NK and T Cell Subtypes in the Endometrium of Patients with Recurrent Pregnancy Loss and Recurrent Implantation Failure: Implications for Pregnancy Success. J. Clin. Med. 2023;12:5585. doi: 10.3390/jcm12175585. [DOI] [PMC free article] [PubMed] [Google Scholar]

68.Morin S.J., Treff N.R., Tao X., Scott R.T., 3rd, Franasiak J.M., Juneau C.R., Maguire M., Scott R.T. Combination of uterine natural killer cell immunoglobulin receptor haplotype and trophoblastic HLA-C ligand influences the risk of pregnancy loss: A retrospective cohort analysis of direct embryo genotyping data from euploid transfers. Fertil. Steril. 2017;107:677–683.e2. doi: 10.1016/j.fertnstert.2016.12.004. [DOI] [PubMed] [Google Scholar]

69.Khalaf W.S., Mahmoud M.R.A., Elkhatib W.F., Hashem H.R., Soliman W.E. Phenotypic characterization of NKT-like cells and evaluation of specifically related cytokines for the prediction of unexplained recurrent miscarriage. Heliyon. 2021;7:e08409. doi: 10.1016/j.heliyon.2021.e08409. [DOI] [PMC free article] [PubMed] [Google Scholar]

70.Xu Q.H., Liu H., Wang L.L., Zhu Q., Zhang Y.J., Muyayalo K.P., Liao A.H. Roles of γδT cells in pregnancy and pregnancy-related complications. Am. J. Reprod. Immunol. 2021;86:e13487. doi: 10.1111/aji.13487. [DOI] [PubMed] [Google Scholar]

71.Li L., Liu Y., Zhou W., Yang C., Feng T., Li H. Human chorionic gonadotrophin indirectly activates peripheral γδT cells to produce interleukin-10 during early pregnancy. Immun. Inflamm. Dis. 2024;12:e1119. doi: 10.1002/iid3.1119. [DOI] [PMC free article] [PubMed] [Google Scholar]

72.Zhang D., Yu Y., Duan T., Zhou Q. The role of macrophages in reproductive-related diseases. Heliyon. 2022;8:e11686. doi: 10.1016/j.heliyon.2022.e11686. [DOI] [PMC free article] [PubMed] [Google Scholar]

73.Nagamatsu T., Schust D.J. The Contribution of Macrophages to Normal and Pathological Pregnancies. Am. J. Reprod. Immunol. 2010;63:460–471. doi: 10.1111/j.1600-0897.2010.00813.x. [DOI] [PubMed] [Google Scholar]

74.Tsao F.Y., Wu M.Y., Chang Y.L., Wu C.T., Ho H.N. M1 macrophages decrease in the deciduae from normal pregnancies but not from spontaneous abortions or unexplained recurrent spontaneous abortions. J. Formos. Med. Assoc. 2018;117:204–211. doi: 10.1016/j.jfma.2017.03.011. [DOI] [PubMed] [Google Scholar]

75.Robertson S.A., Moldenhauer L.M., Green E.S., Care A.S., Hull M.L. Immune determinants of endometrial receptivity: A biological perspective. Fertil. Steril. 2022;117:1107–1120. doi: 10.1016/j.fertnstert.2022.04.023. [DOI] [PubMed] [Google Scholar]

76.Wang W.J., Hao C.F., Lin Q.D. Dysregulation of macrophage activation by decidual regulatory T cells in unexplained recurrent miscarriage patients. J. Reprod. Immunol. 2011;92:97–102. doi: 10.1016/j.jri.2011.08.004. [DOI] [PubMed] [Google Scholar]

77.Quenby S., Bates M., Doig T., Brewster J., Lewis-Jones D.I., Johnson P.M., Vince G. Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum. Reprod. 1999;14:2386–2391. doi: 10.1093/humrep/14.9.2386. [DOI] [PubMed] [Google Scholar]

78.Krop J., Tian X., van der Hoorn M.L., Eikmans M. The Mac Is Back: The Role of Macrophages in Human Healthy and Complicated Pregnancies. Int. J. Mol. Sci. 2023;24:5300. doi: 10.3390/ijms24065300. [DOI] [PMC free article] [PubMed] [Google Scholar]

79.Tremellen K.P., Russell P. The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure. II: Adenomyosis and macrophages. J. Reprod. Immunol. 2012;93:58–63. doi: 10.1016/j.jri.2011.12.001. [DOI] [PubMed] [Google Scholar]

80.Wei R., Lai N., Zhao L., Zhang Z., Zhu X., Guo Q., Chu C., Fu X., Li X. Dendritic cells in pregnancy and pregnancy-associated diseases. Biomed. Pharmacother. 2021;133:110921. doi: 10.1016/j.biopha.2020.110921. [DOI] [PubMed] [Google Scholar]

81.Saito S. Role of immune cells in the establishment of implantation and maintenance of pregnancy and immunomodulatory therapies for patients with repeated implantation failure and recurrent pregnancy loss. Reprod. Med. Biol. 2024;23:e12600. doi: 10.1002/rmb2.12600. [DOI] [PMC free article] [PubMed] [Google Scholar]

82.Liu S., Wei H., Li Y., Huang C., Lian R., Xu J., Chen L., Zeng Y. Downregulation of ILT4+dendritic cells in recurrent miscarriage and recurrent implantation failure. Am. J. Reprod. Immunol. 2018;80:e12998. doi: 10.1111/aji.12998. [DOI] [PubMed] [Google Scholar]

83.Zhu X.X., Yin X.Q., Hei G.Z., Wei R., Guo Q., Zhao L., Zhang Z., Chu C., Fu X.X., Xu K., et al. Increased miR-6875-5p inhibits plasmacytoid dendritic cell differentiation via the STAT3/E2-2 pathway in recurrent spontaneous abortion. Mol. Hum. Reprod. 2021;27:gaab044. doi: 10.1093/molehr/gaab044. [DOI] [PMC free article] [PubMed] [Google Scholar]

84.Huang C., Zhang H., Chen X., Diao L., Lian R., Zhang X., Hu L., Zeng Y. Association of peripheral blood dendritic cells with recurrent pregnancy loss: A case-controlled study. Am. J. Reprod. Immunol. 2016;76:326–332. doi: 10.1111/aji.12550. [DOI] [PubMed] [Google Scholar]

85.Kwiatek M., Gęca T., Krzyżanowski A., Malec A., Kwaśniewska A. Peripheral Dendritic Cells and CD4+CD25+Foxp3+ Regulatory T Cells in the First Trimester of Normal Pregnancy and in Women with Recurrent Miscarriage. PLoS ONE. 2015;10:e0124747. doi: 10.1371/journal.pone.0124747. [DOI] [PMC free article] [PubMed] [Google Scholar]

86.Sivridis E., Giatromanolaki A., Agnantis N., Anastasiadis P. Mast cell distribution and density in the normal uterus--metachromatic staining using lectins. Eur. J. Obstet. Gynecol. Reprod. Biol. 2001;98:109–113. doi: 10.1016/S0301-2115(00)00564-9. [DOI] [PubMed] [Google Scholar]

87.Norrby K. On Connective Tissue Mast Cells as Protectors of Life, Reproduction, and Progeny. Int. J. Mol. Sci. 2024;25:4499. doi: 10.3390/ijms25084499. [DOI] [PMC free article] [PubMed] [Google Scholar]

88.Lampiasi N. Interactions between Macrophages and Mast Cells in the Female Reproductive System. Int. J. Mol. Sci. 2022;23:5414. doi: 10.3390/ijms23105414. [DOI] [PMC free article] [PubMed] [Google Scholar]

89.Derbala Y., Elazzamy H., Bilal M., Reed R., Salazar Garcia M.D., Skariah A., Dambaeva S., Fernandez E., Germain A., Gilman-Sachs A., et al. Mast cell-induced immunopathology in recurrent pregnancy losses. Am J Reprod Immunol. 2019;82:e13128. doi: 10.1111/aji.13128. [DOI] [PubMed] [Google Scholar]

90.McCallion A., Nasirzadeh Y., Lingegowda H., Miller J.E., Khalaj K., Ahn S., Monsanto S.P., Bidarimath M., Sisnett D.J., Craig A.W., et al. Estrogen mediates inflammatory role of mast cells in endometriosis pathophysiology. Front Immunol. 2022;13:961599. doi: 10.3389/fimmu.2022.961599. [DOI] [PMC free article] [PubMed] [Google Scholar]

91.Dunn T.N., Cope D.I., Tang S., Sirupangi T., Parks S.E., Liao Z., Yuan F., Creighton C.J., Masand R.P., Alpuing Radilla L., et al. Inhibition of CSF1R and KIT With Pexidartinib Reduces Inflammatory Signaling and Cell Viability in Endometriosis. Endocrinology. 2024;165:bqae003. doi: 10.1210/endocr/bqae003. [DOI] [PMC free article] [PubMed] [Google Scholar]

92.Blumenthal R.D., Samoszuk M., Taylor A.P., Brown G., Alisauskas R., Goldenberg D.M. Degranulating eosinophils in human endometriosis. Am. J. Pathol. 2020;156:1581–1588. doi: 10.1016/S0002-9440(10)65030-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

93.Hornung D., Dohrn K., Sotlar K., Greb R.R., Wallwiener D., Kiesel L., Taylor R.N. Localization in tissues and secretion of eotaxin by cells from normal endometrium and endometriosis. J. Clin. Endocrinol. Metab. 2000;85:2604–2608. doi: 10.1210/jc.85.7.2604. [DOI] [PubMed] [Google Scholar]

94.Naseri S., Rosenberg-Hasson Y., Maecker H.T., Avrutsky M.I., Blumenthal P.D. A cross-sectional study comparing the inflammatory profile of menstrual effluent vs. peripheral blood. Health Sci. Rep. 2023;6:e1038. doi: 10.1002/hsr2.1038. [DOI] [PMC free article] [PubMed] [Google Scholar]

95.Wang X., Jia Y., Li D., Guo X., Zhou Z., Qi M., Wang G., Wang F. The Abundance and Function of Neutrophils in the Endometriosis Systemic and Pelvic Microenvironment. Mediat. Inflamm. 2023;2023:1481489. doi: 10.1155/2023/1481489. [DOI] [PMC free article] [PubMed] [Google Scholar]

96.Hebeda C.B., Savioli A.C., Scharf P., de Paula-Silva M., Gil C.D., Farsky S.H.P., Sandri S. Neutrophil depletion in the pre-implantation phase impairs pregnancy index, placenta and fetus development. Front. Immunol. 2022;13:969336. doi: 10.3389/fimmu.2022.969336. [DOI] [PMC free article] [PubMed] [Google Scholar]

97.Ghafourian M., Abuhamidy A., Karami N. Increase of peripheral blood TCD8+cells in women with recurrent miscarriage. J. Obstet. Gynaecol. 2013;34:36–39. doi: 10.3109/01443615.2013.817980. [DOI] [PubMed] [Google Scholar]

98.Morita K., Tsuda S., Kobayashi E., Hamana H., Tsuda K., Shima T., Nakashima A., Ushijima A., Kishi H., Saito S. Analysis of TCR Repertoire and PD-1 Expression in Decidual and Peripheral CD8+ T Cells Reveals Distinct Immune Mechanisms in Miscarriage and Preeclampsia. Front. Immunol. 2020;11:1082. doi: 10.3389/fimmu.2020.01082. [DOI] [PMC free article] [PubMed] [Google Scholar]

99.Carbone J., Sarmiento E., Gallego A., Lanio N., Navarro J., Garcia S., Fernández-Cruz E. Peripheral blood T- and B-cell immunophenotypic abnormalities in selected women with unexplained recurrent miscarriage. J. Reprod. Immunol. 2016;113:50–53. doi: 10.1016/j.jri.2015.11.003. [DOI] [PubMed] [Google Scholar]

100.Huang C., Xiang Z., Zhang Y., Li Y., Xu J., Zhang H., Zeng Y., Tu W. NKG2D as a Cell Surface Marker on γδ-T Cells for Predicting Pregnancy Outcomes in Patients With Unexplained Repeated Implantation Failure. Front. Immunol. 2021;12:631077. doi: 10.3389/fimmu.2021.631077. [DOI] [PMC free article] [PubMed] [Google Scholar]

101.Yu L., Wang L., Wang L., Yan S., Chen S., Xu Q., Su D., Wang X. Identification and validation of immune cells and hub genes alterations in recurrent implantation failure: A GEO data mining study. Front. Genet. 2023;13:1094978. doi: 10.3389/fgene.2022.1094978. [DOI] [PMC free article] [PubMed] [Google Scholar]

102.Wang X., Ma Z., Hong Y., Zhao A., Qiu L., Lu P., Lin Q. The Skewed TCR-BV Repertoire Displayed at the Maternal-Fetal Interface of Women with Unexplained Pregnancy Loss. Am. J. Reprod. Immunol. 2005;54:84–95. doi: 10.1111/j.1600-0897.2005.00291.x. [DOI] [PubMed] [Google Scholar]

103.Robertson S.A., Care A.S., Moldenhauer L.M. Regulatory T cells in embryo implantation and the immune response to pregnancy. J. Clin. Investig. 2018;128:4224–4235. doi: 10.1172/JCI122182. [DOI] [PMC free article] [PubMed] [Google Scholar]

104.Yang H., Qiu L., Chen G., Ye Z., Lü C., Lin Q. Proportional change of CD4+CD25+ regulatory T cells in decidua and peripheral blood in unexplained recurrent spontaneous abortion patients. Fertil. Steril. 2008;89:656–661. doi: 10.1016/j.fertnstert.2007.03.037. [DOI] [PubMed] [Google Scholar]

105.Li Q.H., Zhao Q.Y., Yang W.J., Jiang A.F., Ren C.E., Meng Y.H. Beyond Immune Balance: The Pivotal Role of Decidual Regulatory T Cells in Unexplained Recurrent Spontaneous Abortion. J. Inflamm. Res. 2024;17:2697–2710. doi: 10.2147/JIR.S459263. [DOI] [PMC free article] [PubMed] [Google Scholar]

106.Wang W.J., Hao C.F., Qu Q.L., Wang X., Qiu L.H., Lin Q.D. The deregulation of regulatory T cells on interleukin-17-producing T helper cells in patients with unexplained early recurrent miscarriage. Hum. Reprod. 2010;25:2591–2596. doi: 10.1093/humrep/deq198. [DOI] [PubMed] [Google Scholar]

107.Garmendia J.V., Blanca I., Peña M.J., De Sanctis C.V., De Sanctis J.B. Unlocking the Puzzle: Investigating the Role of Interleukin 17 Genetic Polymorphisms, Circulating Lymphocytes, and Serum Levels in Venezuelan Women with Recurrent Pregnancy Loss. Immuno. 2024;4:301–311. doi: 10.3390/immuno4040019. [DOI] [Google Scholar]

108.Heitmann R.J., Weitzel R.P., Feng Y., Segars J.H., Tisdale J.F., Wolff E.F. Maternal T Regulatory Cell Depletion Impairs Embryo Implantation Which Can Be Corrected With Adoptive T Regulatory Cell Transfer. Reprod. Sci. 2017;24:1014–1024. doi: 10.1177/1933719116675054. [DOI] [PMC free article] [PubMed] [Google Scholar]

109.Granne I., Shen M., Rodriguez-Caro H., Chadha G., O’Donnell E., Brosens J.J., Quenby S., Child T., Southcombe J.H. Characterisation of peri-implantation endometrial Treg and identification of an altered phenotype in recurrent pregnancy loss. Mucosal Immunol. 2022;15:120–129. doi: 10.1038/s41385-021-00451-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

110.Moldenhauer L.M., Foyle K.L., Wilson J.J., Wong Y.Y., Sharkey D.J., Green E.S., Barry S.C., Hull M.L., Robertson S.A. A disrupted FOXP3 transcriptional signature underpins systemic regulatory T cell insufficiency in early pregnancy failure. iScience. 2024;27:108994. doi: 10.1016/j.isci.2024.108994. [DOI] [PMC free article] [PubMed] [Google Scholar]

111.Winger E.E., Reed J.L. Low Circulating CD4+ CD25+ Foxp3+ T Regulatory Cell Levels Predict Miscarriage Risk in Newly Pregnant Women with a History of Failure. Am. J. Reprod. Immunol. 2011;66:320–328. doi: 10.1111/j.1600-0897.2011.00992.x. [DOI] [PubMed] [Google Scholar]

112.Jin L.P., Chen Q.Y., Zhang T., Guo P.F., Li D.J. The CD4+CD25 bright regulatory T cells and CTLA-4 expression in peripheral and decidual lymphocytes are down-regulated in human miscarriage. Clin. Immunol. 2009;133:402–410. doi: 10.1016/j.clim.2009.08.009. [DOI] [PubMed] [Google Scholar]

113.Tang C., Hu W. The role of Th17 and Treg cells in normal pregnancy and unexplained recurrent spontaneous abortion (URSA): New insights into immune mechanisms. Placenta. 2023;142:18–26. doi: 10.1016/j.placenta.2023.08.065. [DOI] [PubMed] [Google Scholar]

114.Farshchi M., Abdollahi E., Saghafi N., Hosseini A., Fallahi S., Rostami S., Rostami P., Rafatpanah H., Habibagahi M. Evaluation of Th17 and Treg cytokines in patients with unexplained recurrent pregnancy loss. J. Clin. Transl. Res. 2022;8:256–265. [PMC free article] [PubMed] [Google Scholar]

115.Franasiak J.M., Alecsandru D., Forman E.J., Gemmell L.C., Goldberg J.M., Llarena N., Margolis C., Laven J., Schoenmakers S., Seli E. A review of the pathophysiology of recurrent implantation failure. Fertil. Steril. 2021;116:1436–1448. doi: 10.1016/j.fertnstert.2021.09.014. [DOI] [PubMed] [Google Scholar]

116.Berdiaki A., Vergadi E., Makrygiannakis F., Vrekoussis T., Makrigiannakis A. Repeated implantation failure is associated with increased Th17/Treg cell ratio, during the secretory phase of the human endometrium. J. Reprod. Immunol. 2024;161:104170. doi: 10.1016/j.jri.2023.104170. [DOI] [PubMed] [Google Scholar]

117.Niafar M., Samaie V., Soltani-Zangbar M.S., Motavalli R., Dolati S., Danaii S., Mehdizadeh A., Yousefi M. The association of Treg and Th17 cells development factors and anti-TPO autoantibodies in patients with recurrent pregnancy loss. BMC Res. Notes. 2023;16:302. doi: 10.1186/s13104-023-06579-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

118.Wang W.J., Salazar Garcia M.D., Deutsch G., Sung N., Yang X., He Q., Jubiz G., Bilal M., Dambaeva S., Gilman-Sachs A., et al. PD-1 and PD-L1 expression on T-cell subsets in women with unexplained recurrent pregnancy losses. Am. J. Reprod. Immunol. 2020;83:e13230. doi: 10.1111/aji.13230. [DOI] [PubMed] [Google Scholar]

119.Wang W., Sung N., Gilman-Sachs A., Kwak-Kim J. T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells. Front. Immunol. 2020;11:2025. doi: 10.3389/fimmu.2020.02025. [DOI] [PMC free article] [PubMed] [Google Scholar]

120.Weng J., Couture C., Girard S. Innate and Adaptive Immune Systems in Physiological and Pathological Pregnancy. Biology. 2023;12:402. doi: 10.3390/biology12030402. [DOI] [PMC free article] [PubMed] [Google Scholar]

121.Muzzio D., Zenclussen A.C., Jensen F. The Role of B Cells in Pregnancy: The Good and the Bad. Am. J. Reprod. Immunol. 2013;69:408–412. doi: 10.1111/aji.12079. [DOI] [PubMed] [Google Scholar]

122.Eblen A.C., Gercel-Taylor C., Shields L.B.E., Sanfilippo J.S., Nakajima S.T., Taylor D.D. Alterations in humoral immune responses associated with recurrent pregnancy loss. Fertil. Steril. 2000;73:305–313. doi: 10.1016/S0015-0282(99)00505-1. [DOI] [PubMed] [Google Scholar]

123.Marron K., Walsh D., Harrity C. Detailed endometrial immune assessment of both normal and adverse reproductive outcome populations. J. Assist. Reprod. Genet. 2019;36:199–210. doi: 10.1007/s10815-018-1300-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

124.Vujisić S., Lepej S.Ž., Akšamija A., Jerković L., Sokolić B., Kupešić S., Vince A. B- and T-cells in the Follicular Fluid and Peripheral Blood of Patients Undergoing IVF/ET Procedures. Am. J. Reprod. Immunol. 2004;52:379–385. doi: 10.1111/j.1600-0897.2004.00238.x. [DOI] [PubMed] [Google Scholar]

125.Liu J.C., Zeng Q., Duan Y.G., Yeung W.S.B., Li R.H.W., Ng E.H.Y., Cheung K.W., Zhang Q., Chiu P.C.N. B cells: Roles in physiology and pathology of pregnancy. Front. Immunol. 2024;15:1456171. doi: 10.3389/fimmu.2024.1456171. [DOI] [PMC free article] [PubMed] [Google Scholar]

126.Danaii S., Ghorbani F., Ahmadi M., Abbaszadeh H., Koushaeian L., Soltani-Zangbar M.S., Mehdizadeh A., Hojjat-Farsangi M., Kafil H.S., Aghebati-Maleki L., et al. IL-10-producing B cells play important role in the pathogenesis of recurrent pregnancy loss. Int. Immunopharmacol. 2020;87:106806. doi: 10.1016/j.intimp.2020.106806. [DOI] [PubMed] [Google Scholar]

127.Bronte V., Brandau S., Chen S.H., Colombo M.P., Frey A.B., Greten T.F., Mandruzzato S., Murray P.J., Ochoa A., Ostrand-Rosenberg S., et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 2016;7:12150. doi: 10.1038/ncomms12150. [DOI] [PMC free article] [PubMed] [Google Scholar]

128.Ostrand-Rosenberg S., Sinha P., Figley C., Long R., Park D., Carter D., Clements V.K. Frontline Science: Myeloid-derived suppressor cells (MDSCs) facilitate maternal–fetal tolerance in mice. J. Leukoc. Biol. 2016;101:1091–1101. doi: 10.1189/jlb.1HI1016-306RR. [DOI] [PMC free article] [PubMed] [Google Scholar]

129.Köstlin N., Hofstädter K., Ostermeir A.L., Spring B., Leiber A., Haen S., Abele H., Bauer P., Pollheimer J., Hartl D., et al. Granulocytic Myeloid-Derived Suppressor Cells Accumulate in Human Placenta and Polarize toward a Th2 Phenotype. J. Immunol. 2016;196:1132–1145. doi: 10.4049/jimmunol.1500340. [DOI] [PubMed] [Google Scholar]

130.Bartmann C., Junker M., Segerer S.E., Häusler S.F., Krockenberger M., Kämmerer U. CD33+/HLA-DRnegand CD33+/HLA-DR+/−Cells: Rare Populations in the Human Decidua with Characteristics of MDSC. Am. J. Reprod. Immunol. 2016;75:539–556. doi: 10.1111/aji.12492. [DOI] [PubMed] [Google Scholar]

131.Pan T., Zhong L., Wu S., Cao Y., Yang Q., Cai Z., Cai X., Zhao W., Ma N., Zhang W., et al. 17β-Oestradiol enhances the expansion and activation of myeloid-derived suppressor cells via signal transducer and activator of transcription (STAT)-3 signalling in human pregnancy. Clin. Exp. Immunol. 2016;185:86–97. doi: 10.1111/cei.12790. [DOI] [PMC free article] [PubMed] [Google Scholar]

132.Li C., Zhang X., Kang X., Chen C., Guo F., Wang Q., Zhao A. Upregulated TRAIL and Reduced DcR2 Mediate Apoptosis of Decidual PMN-MDSC in Unexplained Recurrent Pregnancy Loss. Front. Immunol. 2020;11:1345. doi: 10.3389/fimmu.2020.01345. [DOI] [PMC free article] [PubMed] [Google Scholar]

133.Jiang H., Zhu M., Guo P., Bi K., Lu Z., Li C., Zhai M., Wang K., Cao Y. Impaired myeloid-derived suppressor cells are associated with recurrent implantation failure: A case-control study. J. Reprod. Immunol. 2021;145:103316. doi: 10.1016/j.jri.2021.103316. [DOI] [PubMed] [Google Scholar]

134.Marin N.S., Fuente-Muñoz E., Gil-Laborda R., Villegas Á., Alonso-Arenilla B., Cristóbal I., Pilar-Suárez L., Jiménez-Huete A., Calvo M., Sarria B., et al. Myeloid-derived suppressor cells as a potential biomarker for recurrent pregnancy loss and recurrent implantation failure. Am. J. Reprod. Immunol. 2023;90:e13783. doi: 10.1111/aji.13783. [DOI] [PubMed] [Google Scholar]

135.Pantos K., Grigoriadis S., Maziotis E., Pistola K., Xystra P., Pantou A., Kokkali G., Pappas A., Lambropoulou M., Sfakianoudis K., et al. The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature. Int. J. Mol. Sci. 2022;23:2198. doi: 10.3390/ijms23042198. [DOI] [PMC free article] [PubMed] [Google Scholar]

136.Dong X., Zhou M., Li X., Huang H., Sun Y. Gene profiling reveals the role of inflammation, abnormal uterine muscle contraction and vascularity in recurrent implantation failure. Front. Genet. 2023;14:1108805. doi: 10.3389/fgene.2023.1108805. [DOI] [PMC free article] [PubMed] [Google Scholar]

137.Kalu E., Bhaskaran S., Thum M.Y., Vishwanatha R., Croucher C., Sherriff E., Ford B., Bansal A.S. Serial Estimation of Th1:Th2 Cytokines Profile in Women Undergoing In-Vitro Fertilization-Embryo Transfer. Am. J. Reprod. Immunol. 2008;59:206–211. doi: 10.1111/j.1600-0897.2007.00565.x. [DOI] [PubMed] [Google Scholar]

138.Piekarska K., Dratwa M., Radwan P., Radwan M., Bogunia-Kubik K., Nowak I. Pro- and anti-inflammatory cytokines and growth factors in patients undergoing in vitro fertilization procedure treated with prednisone. Front. Immunol. 2023;14:1250488. doi: 10.3389/fimmu.2023.1250488. [DOI] [PMC free article] [PubMed] [Google Scholar]

139.Mukherjee N., Sharma R., Modi D. Immune alterations in recurrent implantation failure. Am. J. Reprod. Immunol. 2022;89:e13563. doi: 10.1111/aji.13563. [DOI] [PubMed] [Google Scholar]

140.Guo L., Guo A., Yang F., Li L., Yan J., Deng X., Dai C., Li Y. Alterations of Cytokine Profiles in Patients With Recurrent Implantation Failure. Front. Endocrinol. 2022;13:949123. doi: 10.3389/fendo.2022.949123. [DOI] [PMC free article] [PubMed] [Google Scholar]

141.Yang X., Tian Y., Zheng L., Luu T., Kwak-Kim J. The Update Immune-Regulatory Role of Pro- and Anti-Inflammatory Cytokines in Recurrent Pregnancy Losses. Int. J. Mol. Sci. 2023;24:132. doi: 10.3390/ijms24010132. [DOI] [PMC free article] [PubMed] [Google Scholar]

142.Kwak-Kim J.Y.H., Chung-Bang H., Ng S., Ntrivalas E., Mangubat C., Beaman K., Beer A., Gilman-Sachs A. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum. Reprod. 2003;18:767–773. doi: 10.1093/humrep/deg156. [DOI] [PubMed] [Google Scholar]

143.Sereshki N., Gharagozloo M., Ostadi V., Ghahiri A., Roghaei M., Mehrabian F., Andalib A., Hassanzadeh A., Hosseini H., Rezaei A.A. Variations in T-helper 17 and Regulatory T Cells during The Menstrual Cycle in Peripheral Blood of Women with Recurrent Spontaneous Abortion. Int. J. Fertil. Steril. 2014;8:59–66. [PMC free article] [PubMed] [Google Scholar]

144.Inagaki N., Stern C., McBain J., Lopata A., Kornman L., Wilkinson D. Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer. Hum. Reprod. 2003;18:608–615. doi: 10.1093/humrep/deg139. [DOI] [PubMed] [Google Scholar]

145.Wang W.J., Zhang H., Chen Z.Q., Zhang W., Liu X.M., Fang J.Y., Liu F.J., Kwak-Kim J. Endometrial TGF-β, IL-10, IL-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis. Reprod. Biol. Endocrinol. 2019;17:2. doi: 10.1186/s12958-018-0444-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

146.Sheikhansari G., Soltani-Zangbar M.S., Pourmoghadam Z., Kamrani A., Azizi R., Aghebati-Maleki L., Danaii S., Koushaeian L., Hojat-Farsangi M., Yousefi M. Oxidative stress, inflammatory settings, and microRNA regulation in the recurrent implantation failure patients with metabolic syndrome. Am. J. Reprod. Immunol. 2019;82:e13170. doi: 10.1111/aji.13170. [DOI] [PubMed] [Google Scholar]

147.O’Hern Perfetto C., Fan X., Dahl S., Krieg S.A., Westphal L.M., Lathi R.B., Nayak N.R. Expression of interleukin-22 in decidua of patients with early pregnancy and unexplained recurrent pregnancy loss. J. Assist. Reprod. Genet. 2015;32:977–984. doi: 10.1007/s10815-015-0481-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

148.Wang W.J., Liu F.J., Qu H.M., Hao C.F., Qu Q.L., Bao H.C., Wang X.R. Regulation of the expression of Th17 cells and regulatory T cells by IL-27 in patients with unexplained early recurrent miscarriage. J. Reprod. Immunol. 2013;99:39–45. doi: 10.1016/j.jri.2013.04.002. [DOI] [PubMed] [Google Scholar]

149.Ma Y., Ma M., Ye S., Liu Y., Zhao X., Wang Y. Association of IL-17 and IL-27 polymorphisms with susceptibility to recurrent pregnancy loss and pre-eclampsia: A systematic review and meta-analysis. Immun. Inflamm. Dis. 2023;11:e1057. doi: 10.1002/iid3.1057. [DOI] [PMC free article] [PubMed] [Google Scholar]

150.Zhao L., Fu J., Ding F., Liu J., Li L., Song Q., Fu Y. IL-33 and Soluble ST2 Are Associated With Recurrent Spontaneous Abortion in Early Pregnancy. Front. Physiol. 2021;12:789829. doi: 10.3389/fphys.2021.789829. [DOI] [PMC free article] [PubMed] [Google Scholar]

151.Yue C., Zhang B., Ying C. Elevated Serum Level of IL-35 Associated with the Maintenance of Maternal-Fetal Immune Tolerance in Normal Pregnancy. PLoS ONE. 2015;10:e0128219. doi: 10.1371/journal.pone.0128219. [DOI] [PMC free article] [PubMed] [Google Scholar]

152.Karaer A., Cigremis Y., Celik E., Urhan Gonullu R. Prokineticin 1 and leukemia inhibitory factor mRNA expression in the endometrium of women with idiopathic recurrent pregnancy loss. Fertil. Steril. 2014;102:1091–1095.e1. doi: 10.1016/j.fertnstert.2014.07.010. [DOI] [PubMed] [Google Scholar]

153.Raghupathy R., Al-Mutawa E., Al-Azemi M., Makhseed M., Azizieh F., Szekeres-Bartho J. Progesterone-induced blocking factor (PIBF) modulates cytokine production by lymphocytes from women with recurrent miscarriage or preterm delivery. J. Reprod. Immunol. 2009;80:91–99. doi: 10.1016/j.jri.2009.01.004. [DOI] [PubMed] [Google Scholar]

154.Kashyap N., Begum A., Ray Das C., Datta R., Verma M.K., Dongre A., Husain S.A., Ahmad Khan L., Deka Bose P. Aberrations in the progesterone pathway and the Th1/Th2 cytokine dichotomy—An evaluation of RPL predisposition in the northeast Indian population. Am. Reprod. Immunol. 2023;90:e13745. doi: 10.1111/aji.13745. [DOI] [PubMed] [Google Scholar]

155.Amjadi F., Zandieh Z., Mehdizadeh M., Aghajanpour S., Raoufi E., Aghamajidi A., Aflatoonian R. The uterine immunological changes may be responsible for repeated implantation failure. J. Reprod. Immunol. 2020;138:103080. doi: 10.1016/j.jri.2020.103080. [DOI] [PubMed] [Google Scholar]

156.Laitinen T. A Set of MHC Haplotypes Found Among Finnish Couples Suffering From Recurrent Spontaneous Abortions. Am. J. Reprod. Immunol. 1993;29:148–154. doi: 10.1111/j.1600-0897.1993.tb00580.x. [DOI] [PubMed] [Google Scholar]

157.Hsiao T.W., Chung M.T., Wen J.Y., Lin Y., Lin L.Y., Tsai Y. HLA sharing and maternal HLA expression in couples with recurrent pregnancy loss in Taiwan. Taiwan J. Obstet. Gynecol. 2022;61:854–857. doi: 10.1016/j.tjog.2021.11.039. [DOI] [PubMed] [Google Scholar]

158.Gharesi-Fard B., Askarinejad-Behbahani R., Behdin S. The effect of HLA-DRB1 sharing between the couples with recurrent pregnancy loss on the pregnancy outcome after leukocyte therapy. Iran. J. Immunol. 2014;11:13–20. [PubMed] [Google Scholar]

159.Wang X.P., Lin Q., Peng L., Ma Z., Zhao A. Association of HLA-DQB1 coding region with unexplained recurrent spontaneous abortion. Chin. Med. J. 2004;117:492–497. [PubMed] [Google Scholar]

160.Ho H.N., Yang Y.S., Hsieh R.P., Lin H.R., Chen S., Huang S., Lee T.Y., Gill T.J. Sharing of human leukocyte antigens in couples with unexplained infertility affects the success of in vitro fertilization and tubal embryo transfer. Am. J. Obstet. Gynecol. 1994;170:63–71. doi: 10.1016/S0002-9378(94)70385-X. [DOI] [PubMed] [Google Scholar]

161.Weckstein L.N., Patrizio P., Balmaceda J.P., Asch R.H., Branch D.W. Human leukocyte antigen compatibility and failure to achieve a viable pregnancy with assisted reproductive technology. Acta Eur. Fertil. 1991;22:103–107. [PubMed] [Google Scholar]

162.Balasch J., Jové I., Martorell J., Gayà A., Vanrell J.A. Histocompatibility in in vitro fertilization couples. Fertil Steril. 1993;59:456–458. doi: 10.1016/S0015-0282(16)55687-8. [DOI] [PubMed] [Google Scholar]

163.Hiby S.E., Regan L., Lo W., Farrell L., Carrington M., Moffett A. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum. Reprod. 2008;23:972–976. doi: 10.1093/humrep/den011. [DOI] [PubMed] [Google Scholar]

164.Hiby S.E., Apps R., Sharkey A.M., Farrell L.E., Gardner L., Mulder A., Claas F.H., Walker J.J., Redman C.W., Morgan L., et al. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J. Clin. Investig. 2010;120:4102–4110. doi: 10.1172/JCI43998. [DOI] [PMC free article] [PubMed] [Google Scholar]

165.Yang X., Meng T. Killer-cell immunoglobulin-like receptor/human leukocyte antigen-C combination and ‘great obstetrical syndromes’ (Review) Exp Ther Med. 2021;22:1178. doi: 10.3892/etm.2021.10612. [DOI] [PMC free article] [PubMed] [Google Scholar]

166.Gil Laborda R., de Frías E.R., Subhi-Issa N., de Albornoz E.C., Meliá E., Órdenes M., Verdú V., Vidal J., Suárez E., Santillán I., et al. Centromeric AA motif in KIR as an optimal surrogate marker for precision definition of alloimmune reproductive failure. Sci. Rep. 2024;14:3354. doi: 10.1038/s41598-024-53766-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

167.Dahl M., Djurisic S., Hviid T.V. The many faces of human leukocyte antigen-G: Relevance to the fate of pregnancy. J. Immunol. Res. 2014;2014:591489. doi: 10.1155/2014/591489. [DOI] [PMC free article] [PubMed] [Google Scholar]

168.Fan W., Huang Z., Li S., Xiao Z. The HLA-G 14-bp polymorphism and recurrent implantation failure: A meta-analysis. J. Assist. Reprod. Genet. 2017;34:1559–1565. doi: 10.1007/s10815-017-0994-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

169.Hu L., He D., Zeng H. Association of parental HLA-G polymorphisms with soluble HLA-G expressions and their roles on recurrent implantation failure: A systematic review and meta-analysis. Front. Immunol. 2022;13:988370. doi: 10.3389/fimmu.2022.988370. [DOI] [PMC free article] [PubMed] [Google Scholar]

170.Nowak I., Wilczyńska K., Radwan P., Wiśniewski A., Krasiński R., Radwan M., Wilczyński J.R., Malinowski A., Kuśnierczyk P. Association of Soluble HLA-G Plasma Level and HLA-G Genetic Polymorphism With Pregnancy Outcome of Patients Undergoing in vitro Fertilization Embryo Transfer. Front. Immunol. 2020;10:2982. doi: 10.3389/fimmu.2019.02982. [DOI] [PMC free article] [PubMed] [Google Scholar]

171.Zych M., Roszczyk A., Kniotek M., Dąbrowski F., Zagożdżon R. Differences in Immune Checkpoints Expression (TIM-3 and PD-1) on T Cells in Women with Recurrent Miscarriages-Preliminary Studies. J. Clin. Med. 2021;10:4182. doi: 10.3390/jcm10184182. [DOI] [PMC free article] [PubMed] [Google Scholar]

172.Zych M., Roszczyk A., Dąbrowski F., Kniotek M., Zagożdżon R. Soluble Forms of Immune Checkpoints and Their Ligands as Potential Biomarkers in the Diagnosis of Recurrent Pregnancy Loss-A Preliminary Study. Int. J. Mol. Sci. 2023;25:499. doi: 10.3390/ijms25010499. [DOI] [PMC free article] [PubMed] [Google Scholar]

173.Esparvarinha M., Madadi S., Aslanian-Kalkhoran L., Nickho H., Dolati S., Pia H., Danaii S., Taghavi S., Yousefi M. Dominant immune cells in pregnancy and pregnancy complications: T helper cells (TH1/TH2, TH17/Treg cells), NK cells, MDSCs, and the immune checkpoints. Cell Biol. Int. 2023;47:507–519. doi: 10.1002/cbin.11955. [DOI] [PubMed] [Google Scholar]

174.Qian C., Pan C., Liu J., Wu L., Pan J., Liu C., Zhang H. Differential expression of immune checkpoints (OX40/OX40L and PD-1/PD-L1) in decidua of unexplained recurrent spontaneous abortion women. Hum. Immunol. 2024;85:110745. doi: 10.1016/j.humimm.2023.110745. [DOI] [PubMed] [Google Scholar]

175.Zych M., Kniotek M., Roszczyk A., Dąbrowski F., Jędra R., Zagożdżon R. Surface Immune Checkpoints as Potential Biomarkers in Physiological Pregnancy and Recurrent Pregnancy Loss. Int. J. Mol. Sci. 2024;25:9378. doi: 10.3390/ijms25179378. [DOI] [PMC free article] [PubMed] [Google Scholar]

176.Opatrny L., David M., Kahn S.R., Shrier I., Rey E. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: A metaanalysis. J. Rheumatol. 2006;33:2214–2221. [PubMed] [Google Scholar]

177.Thangaratinam S., Tan A., Knox E., Kilby M.D., Franklyn J., Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: Metaanalysis of evidence. BMJ. 2011;342:1–8. doi: 10.1136/bmj.d2616. [DOI] [PMC free article] [PubMed] [Google Scholar]

178.Cavalcante M.B., Cavalgante C.T., Sarno M., Da Silva A., Barini R. Antinuclear antibodies and recurrent miscarriage: Systematic review and meta-analysis. Am. J. Reprod. Immunol. 2020;83:13215. doi: 10.1111/aji.13215. [DOI] [PubMed] [Google Scholar]

179.Chen S., Yang G., Wu P., Sun Y., Dai F., He Y., Qian H., Liu Y., Shi G. Antinuclear antibodies positivity is a risk factor of recurrent pregnancy loss: A meta-analysis. Semin. Arthritis Rheum. 2020;50:534–543. doi: 10.1016/j.semarthrit.2020.03.016. [DOI] [PubMed] [Google Scholar]

180.Alijotas-Reig J., Esteve-Valverde E., Ferrer-Oliveras R., Llurba E., Gris J.M. Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review. Clin. Rev. Allergy Immunol. 2017;53:40–53. doi: 10.1007/s12016-016-8596-x. [DOI] [PubMed] [Google Scholar]

181.Lockwood C.J., Romero R., Feinberg R.F., Clyne L.P., Coster B., Hobbins J.C. The prevalence and biologic significance of lupus anticoagulant and antic ardiolipin antibodies in a general obstetric population. Am. J. Obstet. Gynecol. 1989;161:369–373. doi: 10.1016/0002-9378(89)90522-X. [DOI] [PubMed] [Google Scholar]

182.Bahar A.M., Kwak J.Y.H., Beer A.E., Kim J.H., Nelson L.A., Beaman K.D., Gilman-Sachs A. Antibodies to phospholipids and nuclear antigens in non-pregnant women with unexplained spontaneous recurrent abortions. J. Reprod. Immunol. 1993;24:213–222. doi: 10.1016/0165-0378(93)90076-T. [DOI] [PubMed] [Google Scholar]

183.Kwak J.Y.H., Beer A.E., Cubillos J., Muñoz Sandoval P., Mendoza J., Espinel F. Biological Basis of Fetoplacental Antigenic Determinants in the Induction of the Antiphospholipid Antibody Syndrome and Recurrent Pregnancy Loss. Ann. N. Y. Acad. Sci. 1994;731:242–245. doi: 10.1111/j.1749-6632.1994.tb55776.x. [DOI] [PubMed] [Google Scholar]

184.Rai R.S., Regan L., Clifford K., Pickering W., Dave M., Mackie I., McNally T., Cohen H. Immunology: Antiphospholipid antibodies and β2-glycoprotein-I in 500 women with recurrent miscarriage: Results of a comprehensive screening approach. Hum. Reprod. 1995;10:2001–2005. doi: 10.1093/oxfordjournals.humrep.a136224. [DOI] [PubMed] [Google Scholar]

185.Del Porto F., Ferrero S., Cifani N., Sesti G., Proietta M. Antiphospholipid antibodies and idiopathic infertility. Lupus. 2022;31:347–353. doi: 10.1177/09612033221076735. [DOI] [PubMed] [Google Scholar]

186.D’Ippolito S., Ticconi C., Tersigni C., Garofalo S., Martino C., Lanzone A., Scambia G., Di Simone N. The pathogenic role of autoantibodies in recurrent pregnancy loss. Am. J. Reprod. Immunol. 2019;83:e13200. doi: 10.1111/aji.13200. [DOI] [PubMed] [Google Scholar]

187.Gibbins K.J., Mumford S.L., Sjaarda L.A., Branch D.W., Perkins N.J., Ye A., Schisterman E.F., Silver R.M. Preconception antiphospholipid antibodies and risk of subsequent early pregnancy loss. Lupus. 2018;27:1437–1445. doi: 10.1177/0961203318776089. [DOI] [PMC free article] [PubMed] [Google Scholar]

188.Papadimitriou E., Boutzios G., Mathioudakis A.G., Vlahos N.F., Vlachoyiannopoulos P., Mastorakos G. Presence of antiphospholipid antibodies is associated with increased implantation failure following in vitro fertilization technique and embryo transfer: A systematic review and meta-analysis. PLoS ONE. 2022;17:e0260759. doi: 10.1371/journal.pone.0260759. [DOI] [PMC free article] [PubMed] [Google Scholar]

189.Jarne-Borràs M., Miró-Mur F., Anunciación-Llunell A., Alijotas-Reig J. Antiphospholipid antibodies in women with recurrent embryo implantation failure: A systematic review and meta-analysis. Autoimmun. Rev. 2022;21:103101. doi: 10.1016/j.autrev.2022.103101. [DOI] [PubMed] [Google Scholar]

190.Tan X.F., Xu L., Li T.T., Wu Y.T., Ma W.W., Ding J.Y., Dong H.L. Serum antiphospholipid antibody status may not be associated with the pregnancy outcomes of patients undergoing in vitro fertilization. Medicine. 2022;101:e29146. doi: 10.1097/MD.0000000000029146. [DOI] [PMC free article] [PubMed] [Google Scholar]

191.Tan X., Ding J., Pu D., Wu J. Anti-phospholipid antibody may reduce endometrial receptivity during the window of embryo implantation. J. Gynecol. Obstet. Hum. Reprod. 2021;50:101912. doi: 10.1016/j.jogoh.2020.101912. [DOI] [PubMed] [Google Scholar]

192.Matalon S.T., Blank M.B., Ornoy A., Shoenfeld Y. The Association Between Anti-Thyroid Antibodies and Pregnancy Loss. Am. J. Reprod. Immunol. Microbiol. 2001;45:72–77. doi: 10.1111/j.8755-8920.2001.450202.x. [DOI] [PubMed] [Google Scholar]

193.Valeff N.J., Ventimiglia M.S., Diao L., Jensen F. Lupus and recurrent pregnancy loss: The role of female sex hormones and B cells. Front. Endocrinol. 2023;14:1233883. doi: 10.3389/fendo.2023.1233883. [DOI] [PMC free article] [PubMed] [Google Scholar]

194.Gao R., Zeng X., Qin L. Systemic autoimmune diseases and recurrent pregnancy loss: Research progress in diagnosis and treatment. Chin. Med. J. 2021;134:2140–2142. doi: 10.1097/CM9.0000000000001691. [DOI] [PMC free article] [PubMed] [Google Scholar]

195.Mankee A., Petri M., Magder L.S. Lupus anticoagulant, disease activity and low complement in the first trimester are predictive of pregnancy loss. Lupus Sci. Med. 2015;2:e000095. doi: 10.1136/lupus-2015-000095. [DOI] [PMC free article] [PubMed] [Google Scholar]

196.Ticconi C., Inversetti A., Logruosso E., Ghio M., Casadei L., Selmi C., Di Simone N. Antinuclear antibodies positivity in women in reproductive age: From infertility to adverse obstetrical outcomes—A meta-analysis. J. Reprod. Immunol. 2023;155:103794. doi: 10.1016/j.jri.2022.103794. [DOI] [PubMed] [Google Scholar]

197.Hardy C.J., Palmer B.P., Morton S.J., Muir K.R., Powell R.J. Pregnancy outcome and family size in systemic lupus erythematosus: A case-control study. Rheumatology. 1999;38:559–563. doi: 10.1093/rheumatology/38.6.559. [DOI] [PubMed] [Google Scholar]

198.Singh M., Fayaz F.F.A., Wang J., Wambua S., Subramanian A., Reynolds J.A., Nirantharakumar K., Crowe F., MuM-PreDiCT Pregnancy complications and autoimmune diseases in women: Systematic review and meta-analysis. BMC Med. 2024;22:339. doi: 10.1186/s12916-024-03550-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

199.Motak-Pochrzest H., Malinowski A. Does autoimmunity play a role in the risk of implantation failures? Neuro Endocrinol. Lett. 2018;38:575–578. [PubMed] [Google Scholar]

200.Salmeri N., Gennarelli G., Vanni V.S., Ferrari S., Ruffa A., Rovere-Querini P., Pagliardini L., Candiani M., Papaleo E. Concomitant Autoimmunity in Endometriosis Impairs Endometrium-Embryo Crosstalk at the Implantation Site: A Multicenter Case-Control Study. J. Clin. Med. 2023;12:3557. doi: 10.3390/jcm12103557. [DOI] [PMC free article] [PubMed] [Google Scholar]

201.Ballester C., Grobost V., Roblot P., Pourrat O., Pierre F., Laurichesse-Delmas H., Gallot D., Aubard Y., Bezanahary H., Fauchais A.L. Pregnancy and primary Sjögren’s syndrome: Management and outcomes in a multicentre retrospective study of 54 pregnancies. Scand. J. Rheumatol. 2017;46:56–63. doi: 10.3109/03009742.2016.1158312. [DOI] [PubMed] [Google Scholar]

202.Gupta S., Gupta N. Sjögren Syndrome and Pregnancy: A Literature Review. Perm J. 2017;21:16-047. doi: 10.7812/TPP/16-047. [DOI] [PMC free article] [PubMed] [Google Scholar]

203.Imbroane M.R., LeMoine F., Gibson K.S. Autoimmune Condition Diagnosis Following Recurrent Pregnancy Loss. Am. J. Reprod. Immunol. 2024;92:e70006. doi: 10.1111/aji.70006. [DOI] [PubMed] [Google Scholar]

204.Masucci L., D’Ippolito S., De Maio F., Quaranta G., Mazzarella R., Bianco D.M., Castellani R., Inversetti A., Sanguinetti M., Gasbarrini A., et al. Celiac Disease Predisposition and Genital Tract Microbiota in Women Affected by Recurrent Pregnancy Loss. Nutrients. 2023;15:221. doi: 10.3390/nu15010221. [DOI] [PMC free article] [PubMed] [Google Scholar]

205.Arvanitakis K., Siargkas A., Germanidis G., Dagklis T., Tsakiridis I. Adverse pregnancy outcomes in women with celiac disease: A systematic review and meta-analysis. Ann. Gastroenterol. 2023;36:12–24. doi: 10.20524/aog.2022.0764. [DOI] [PMC free article] [PubMed] [Google Scholar]

206.Tersigni C., Castellani R., de Waure C., Fattorossi A., De Spirito M., Gasbarrini A., Scambia G., Di Simone N. Celiac disease and reproductive disorders: Meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum. Reprod. Update. 2014;20:582–593. doi: 10.1093/humupd/dmu007. [DOI] [PubMed] [Google Scholar]

207.Saccone G., Berghella V., Sarno L., Maruotti G.M., Cetin I., Greco L., Khashan A.S., McCarthy F., Martinelli D., Fortunato F., et al. Celiac disease and obstetric complications: A systematic review and meta-analysis. Am. J. Obstet. Gynecol. 2016;214:225–234. doi: 10.1016/j.ajog.2015.09.080. [DOI] [PubMed] [Google Scholar]

208.Di Simone N., Silano M., Castellani R., Di Nicuolo F., D’Alessio M.C., Franceschi F., Tritarelli A., Leone A.M., Tersigni C., Gasbarrini G., et al. Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro. Am. J. Gastroenterol. 2010;105:2254–2261. doi: 10.1038/ajg.2010.233. [DOI] [PubMed] [Google Scholar]

209.Di Simone N., De Spirito M., Di Nicuolo F., Tersigni C., Castellani R., Silano M., Maulucci G., Papi M., Marana R., Scambia G., et al. Potential new mechanisms of placental damage in celiac disease: Anti-transglutaminase antibodies impair human endometrial angiogenesis. Biol. Reprod. 2013;89:88. doi: 10.1095/biolreprod.113.109637. [DOI] [PubMed] [Google Scholar]

210.D’Ippolito S., Gasbarrini A., Castellani R., Rocchetti S., Sisti L.G., Scambia G., Di Simone N. Human leukocyte antigen (HLA) DQ2/DQ8 prevalence in recurrent pregnancy loss women. Autoimmun. Rev. 2016;15:638–643. doi: 10.1016/j.autrev.2016.02.009. [DOI] [PubMed] [Google Scholar]

211.Królik M., Wrześniak M., Jezela-Stanek A. Possible effect of the HLA-DQ2/DQ8 polymorphism on autoimmune parameters and lymphocyte subpopulation in recurrent pregnancy losses. J. Reprod. Immunol. 2022;149:103467. doi: 10.1016/j.jri.2021.103467. [DOI] [PubMed] [Google Scholar]

212.Huang C., Liang P., Diao L., Liu C., Chen X., Li G., Chen C., Zeng Y. Thyroid Autoimmunity is Associated with Decreased Cytotoxicity T Cells in Women with Repeated Implantation Failure. Int. J. Environ. Res. Public Health. 2015;12:10352–10361. doi: 10.3390/ijerph120910352. [DOI] [PMC free article] [PubMed] [Google Scholar]

213.Huisman P., Krogh J., Nielsen C.H., Nielsen H.S., Feldt-Rasmussen U., Bliddal S. Thyroglobulin antibodies in women with recurrent pregnancy loss: A Systematic Review and Meta-Analysis. Thyroid. 2023;33:1287–1301. doi: 10.1089/thy.2023.0292. [DOI] [PubMed] [Google Scholar]

214.Zhong Y., Ying Y., Wu H., Zhou C., Xu Y., Wang Q., Li J., Shen X., Jin L. Relationship between Antithyroid Antibody and Pregnancy Outcome following in Vitro Fertilization and Embryo Transfer. Int. J. Med. Sci. 2012;9:121–125. doi: 10.7150/ijms.3467. [DOI] [PMC free article] [PubMed] [Google Scholar]

215.Abdolmohammadi-Vahid S., Danaii S., Hamdi K., Jadidi-Niaragh F., Ahmadi M., Yousefi M. Novel immunotherapeutic approaches for treatment of infertility. Biomed. Pharmacother. 2016;84:1449–1459. doi: 10.1016/j.biopha.2016.10.062. [DOI] [PubMed] [Google Scholar]

216.Stewart-Akers A.M., Krasnow J.S., Brekosky J., Deloia J.A. Endometrial Leukocytes Are Altered Numerically and Functionally in Women with Implantation Defects. Am. J. Reprod. Immunol. 1998;39:1–11. doi: 10.1111/j.1600-0897.1998.tb00326.x. [DOI] [PubMed] [Google Scholar]

217.Dhillon-Smith R.K., Middleton L.J., Sunner K.K., Cheed V., Baker K., Farrell-Carver S., Bender-Atik R., Agrawal R., Bhatia K., Edi-Osagie E., et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N. Engl. J. Med. 2019;380:1316–1325. doi: 10.1056/NEJMoa1812537. [DOI] [PubMed] [Google Scholar]

218.van Dijk M.M., Vissenberg R., Fliers E., van der Post J.A.M., van der Hoorn M.P., de Weerd S., Kuchenbecker W.K., Hoek A., Sikkema J.M., Verhoeve H.R., et al. Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10:322–329. doi: 10.1016/S2213-8587(22)00045-6. [DOI] [PubMed] [Google Scholar]

219.Leng T., Li X., Zhang H. Levothyroxine treatment for subclinical hypothyroidism improves the rate of live births in pregnant women with recurrent pregnancy loss: A randomized clinical trial. Gynecol. Endocrinol. 2022;38:488–494. doi: 10.1080/09513590.2022.2063831. [DOI] [PubMed] [Google Scholar]

220.Rao M., Zeng Z., Zhao S., Tang L. Effect of levothyroxine supplementation on pregnancy outcomes in women with subclinical hypothyroidism and thyroid autoimmunity undergoing in vitro fertilization/intracytoplasmic sperm injection: An updated meta-analysis of randomized controlled trials. Reprod. Biol. Endocrinol. 2018;16:92. doi: 10.1186/s12958-018-0410-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

221.Yu M., Long Y., Wang Y., Zhang R., Tao L. Effect of levothyroxine on the pregnancy outcomes in recurrent pregnancy loss women with subclinical hypothyroidism and thyroperoxidase antibody positivity: A systematic review and meta-analysis. J. Matern.-Fetal Neonatal Med. 2023;36:2233039. doi: 10.1080/14767058.2023.2233039. [DOI] [PubMed] [Google Scholar]

222. [(accessed on 19 January 2025)]. Available online: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Recurrent-pregnancy-loss.

223.Gaál Z. Role of microRNAs in Immune Regulation with Translational and Clinical Applications. Int. J. Mol. Sci. 2024;25:1942. doi: 10.3390/ijms25031942. [DOI] [PMC free article] [PubMed] [Google Scholar]

224.Dong J., Warner L.M., Lin L.L., Chen M.C., O’Connell R.M., Lu L.F. miR-155 promotes T reg cell development by safeguarding medullary thymic epithelial cell maturation. J. Exp. Med. 2021;218:e20192423. doi: 10.1084/jem.20192423. [DOI] [PMC free article] [PubMed] [Google Scholar]

225.Zolfaghari M.A., Motavalli R., Soltani-Zangbar M.S., Parhizkar F., Danaii S., Aghebati-Maleki L., Noori M., Dolati S., Ahmadi M., Samadi Kafil H., et al. A new approach to the preeclampsia puzzle; MicroRNA-326 in CD4+ lymphocytes might be as a potential suspect. J. Reprod. Immunol. 2021;145:103317. doi: 10.1016/j.jri.2021.103317. [DOI] [PubMed] [Google Scholar]

226.Winger E.E., Reed J.L., Ji X. First-trimester maternal cell microRNA is a superior pregnancy marker to immunological testing for predicting adverse pregnancy outcome. J. Reprod. Immunol. 2015;110:22–35. doi: 10.1016/j.jri.2015.03.005. [DOI] [PubMed] [Google Scholar]

227.Patronia M.M., Potiris A., Mavrogianni D., Drakaki E., Karampitsakos T., Machairoudias P., Topis S., Zikopoulos A., Vrachnis D., Moustakli E., et al. The Expression of microRNAs and Their Involvement in Recurrent Pregnancy Loss. J. Clin. Med. 2024;13:3361. doi: 10.3390/jcm13123361. [DOI] [PMC free article] [PubMed] [Google Scholar]

228.Xu N., Zhou X., Shi W., Ye M., Cao X., Chen S., Xu C. Integrative analysis of circulating microRNAs and the placental transcriptome in recurrent pregnancy loss. Front. Physiol. 2022;13:893744. doi: 10.3389/fphys.2022.893744. [DOI] [PMC free article] [PubMed] [Google Scholar]

229.Wang X., Li B., Wang J., Lei J., Liu C., Ma Y., Zhao H. Evidence that miR-133a causes recurrent spontaneous abortion by reducing HLA-G expression. Reprod. Biomed. Online. 2012;25:415–424. doi: 10.1016/j.rbmo.2012.06.022. [DOI] [PubMed] [Google Scholar]

230.Li L., Feng T., Zhou W., Liu Y., Li H. miRNAs in decidual NK cells: Regulators worthy of attention during pregnancy. Reprod. Biol. Endocrinol. 2021;19:150. doi: 10.1186/s12958-021-00812-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

231.Guo C., Yin X., Yao S. The effect of MicroRNAs variants on idiopathic recurrent pregnancy loss. J. Assist. Reprod. Genet. 2023;40:1589–1595. doi: 10.1007/s10815-023-02827-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

232.Thapliyal A., Tomar A.K., Naglot S., Dhiman S., Datta S.K., Sharma J.B., Singh N., Yadav S. Exploring Differentially Expressed Sperm miRNAs in Idiopathic Recurrent Pregnancy Loss and Their Association with Early Embryonic Development. Noncoding RNA. 2024;10:41. doi: 10.3390/ncrna10040041. [DOI] [PMC free article] [PubMed] [Google Scholar]

233.Odendaal J., Black N., Bennett P.R., Brosens J., Quenby S., MacIntyre D.A. The endometrial microbiota and early pregnancy loss. Hum. Reprod. 2024;39:638–646. doi: 10.1093/humrep/dead274. [DOI] [PMC free article] [PubMed] [Google Scholar]

234.Gao X., Louwers Y.V., Laven E., Schoenmakers S. Clinical Relevance of Vaginal and Endometrial Microbiome Investigation in Women with Repeated Implantation Failure and Recurrent Pregnancy Loss. Int. J. Mol. Sci. 2024;25:622. doi: 10.3390/ijms25010622. [DOI] [PMC free article] [PubMed] [Google Scholar]

235.Soyer Caliskan C., Yurtcu N., Celik S., Sezer O., Kilic S.S., Cetin A. Derangements of vaginal and cervical canal microbiota determined with real-time PCR in women with recurrent miscarriages. J. Obstet. Gynaecol. 2022;42:2105–2114. doi: 10.1080/01443615.2022.2033183. [DOI] [PubMed] [Google Scholar]

236.Al-Memar M., Bobdiwala S., Fourie H., Mannino R., Lee Y.S., Smith A., Marchesi J.R., Timmerman D., Bourne T., Bennett P.R., et al. The association between vaginal bacterial composition and miscarriage: A nested case-control study. BJOG. 2020;127:264–274. doi: 10.1111/1471-0528.15972. [DOI] [PMC free article] [PubMed] [Google Scholar]

237.Grewal K., Lee Y.S., Smith A., Brosens J.J., Bourne T., Al-Memar M., Kundu S., MacIntyre D.A., Bennett P.R. Chromosomally normal miscarriage is associated with vaginal dysbiosis and local inflammation. BMC Med. 2022;20:38. doi: 10.1186/s12916-021-02227-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

238.Peuranpää P., Holster T., Saqib S., Kalliala I., Tiitinen A., Salonen A., Hautamäki H. Female reproductive tract microbiota and recurrent pregnancy loss: A nested case-control study. Reprod. BioMed. Online. 2022;45:1021–1031. doi: 10.1016/j.rbmo.2022.06.008. [DOI] [PubMed] [Google Scholar]

239.Vomstein K., Reider S., Böttcher B., Watschinger C., Kyvelidou C., Tilg H., Moschen A.R., Toth B. Uterine microbiota plasticity during the menstrual cycle: Differences between healthy controls and patients with recurrent miscarriage or implantation failure. J. Reprod. Immunol. 2022;151:103634. doi: 10.1016/j.jri.2022.103634. [DOI] [PubMed] [Google Scholar]

240.Moreno I., Garcia-Grau I., Perez-Villaroya D., Gonzalez-Monfort M., Bahçeci M., Barrionuevo M.J., Taguchi S., Puente E., Dimattina M., Lim M.W., et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients. Microbiome. 2022;10:1. doi: 10.1186/s40168-021-01184-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

241.Shi Y., Yamada H., Sasagawa Y., Tanimura K., Deguchi M. Uterine endometrium microbiota and pregnancy outcome in women with recurrent pregnancy loss. J. Reprod. Immunol. 2022;152:103653. doi: 10.1016/j.jri.2022.103653. [DOI] [PubMed] [Google Scholar]

242.Wang L., Chen J., He L., Liu H., Liu Y., Luan Z., Li H., Liu W., Luo M. Association between the vaginal and uterine microbiota and the risk of early embryonic arrest. Front. Microbiol. 2023;14:1137869. doi: 10.3389/fmicb.2023.1137869. [DOI] [PMC free article] [PubMed] [Google Scholar]

243. [(accessed on 19 January 2025)]. Available online: https://www.asrm.org/practice-guidance/practice-committee-documents/evaluation-and-treatment-of-recurrent-pregnancy-loss-a-committee-opinion-2012.

244.Quenby S., Kalumbi C., Bates M., Farquharson R., Vince G. Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertil. Steril. 2005;84:980–984. doi: 10.1016/j.fertnstert.2005.05.012. [DOI] [PubMed] [Google Scholar]

245.Gomaa M.F., Elkholy A.G., El-Said M.M., Abdel-Salam N.E. Combined oral prednisolone and heparin versus heparin: The effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch. Gynecol. Obstet. 2014;290:757–762. doi: 10.1007/s00404-014-3262-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

246.Rezayat F., Esmaeil N., Rezaei A., Sherkat R. Contradictory Effect of Lymphocyte Therapy and Prednisolone Therapy on CD3+CD8+CD56+ Natural Killer T Population in Women with Recurrent Spontaneous Abortion. J. Hum. Reprod. Sci. 2023;16:246. doi: 10.4103/jhrs.jhrs_8_23. [DOI] [PMC free article] [PubMed] [Google Scholar]

247.Tang A.W., Alfirevic Z., Turner M.A., Drury J.A., Small R., Quenby S. A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. Hum. Reprod. 2013;28:1743–1752. doi: 10.1093/humrep/det117. [DOI] [PubMed] [Google Scholar]

248.Boomsma C.M., Kamath M.S., Keay S.D., Macklon N.S. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database Syst. Rev. 2022;6:CD005996. doi: 10.1002/14651858.CD005996. [DOI] [PMC free article] [PubMed] [Google Scholar]

249.Cooper S., Laird S.M., Mariee N., Li T.C., Metwally M. The effect of prednisolone on endometrial uterine NK cell concentrations and pregnancy outcome in women with reproductive failure. A retrospective cohort study. J. Reprod. Immunol. 2019;131:1–6. doi: 10.1016/j.jri.2018.10.001. [DOI] [PubMed] [Google Scholar]

250.Dan S., Wei W., Yichao S., Hongbo C., Shenmin Y., Jiaxiong W., Hong L. Effect of Prednisolone Administration on Patients with Unexplained Recurrent Miscarriage and in Routine Intracytoplasmic Sperm Injection: A Meta-Analysis. Am. J. Reprod. Immunol. 2015;74:89–97. doi: 10.1111/aji.12373. [DOI] [PubMed] [Google Scholar]

251.He Y., Tang R., Yu H., Mu H., Jin H., Dong J., Wang W., Wang L., Chen S., Wang X. Comparative effectiveness and safety of 36 therapies or interventions for pregnancy outcomes with recurrent implantation failure: A systematic review and network meta-analysis. J. Assist. Reprod. Genet. 2023;40:2343–2356. doi: 10.1007/s10815-023-02923-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

252.Huang Q., Wu H., Li M., Yang Y., Fu X. Prednisone improves pregnancy outcome in repeated implantation failure by enhance regulatory T cells bias. J. Reprod. Immunol. 2021;143:103245. doi: 10.1016/j.jri.2020.103245. [DOI] [PubMed] [Google Scholar]

253.Hasegawa I., Yamanoto Y., Suzuki M., Murakawa H., Kurabayashi T., Takakuwa K., Tanaka K. Prednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization. Fertil. Steril. 1998;70:1044–1048. doi: 10.1016/S0015-0282(98)00343-4. [DOI] [PubMed] [Google Scholar]

254.Fan J., Zhong Y., Chen C. Combined treatment of prednisone and aspirin, starting before ovulation induction, may improve reproductive outcomes in ANA-positive patients. Am. J. Reprod. Immunol. 2016;76:391–395. doi: 10.1111/aji.12559. [DOI] [PubMed] [Google Scholar]

255.Ando T., Suganuma N., Furuhashi M., Asada Y., Kondo I., Tsutsumi Y. Successful glucocorticoid treatment for patients with abnormal autoimmunity on in vitro fertilization and embryo transfer. J. Assist. Reprod. Genet. 1996;13:776–781. doi: 10.1007/BF02066497. [DOI] [PubMed] [Google Scholar]

256.Sun Y., Cui L., Lu Y., Tan J., Dong X., Ni T., Yan J., Guan Y., Hao G., Liu J.Y., et al. Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization. JAMA. 2023;329:1460. doi: 10.1001/jama.2023.5302. [DOI] [PMC free article] [PubMed] [Google Scholar]

257.Bramham K., Thomas M., Nelson-Piercy C., Khamashta M., Hunt B.J. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117:6948–6951. doi: 10.1182/blood-2011-02-339234. [DOI] [PubMed] [Google Scholar]

258.Riancho-Zarrabeitia L., Lopez-Marin L., Cacho P.M., López-Hoyos M., Barrio R.D., Haya A., Martínez-Taboada V.M. Treatment with low-dose prednisone in refractory obstetric antiphospholipid syndrome: A retrospective cohort study and meta-analysis. Lupus. 2022;31:808–819. doi: 10.1177/09612033221091401. [DOI] [PubMed] [Google Scholar]

259.Forges T., Monnier-Barbarino P., Guillet-May F., Faure G.C., Béné M.C. Corticosteroids in patients with antiovarian antibodies undergoing in vitro fertilization: A prospective pilot study. Eur. J. Clin. Pharmacol. 2006;62:699–705. doi: 10.1007/s00228-006-0169-0. [DOI] [PubMed] [Google Scholar]

260.Bandoli G., Palmsten K., Forbess Smith C.J., Chambers C.D. A review of systemic corticosteroid use in pregnancy and the risk of select pregnancy and birth outcomes. Rheum. Dis. Clin. N. Am. 2017;43:489–502. doi: 10.1016/j.rdc.2017.04.013. [DOI] [PMC free article] [PubMed] [Google Scholar]

261.Hooper A., Bacal V., Bedaiwy M.A. Does adding hydroxychloroquine to empiric treatment improve the live birth rate in refractory obstetrical antiphospholipid syndrome? A systematic review. Am. J. Reprod. Immunol. 2023;90:e13761. doi: 10.1111/aji.13761. [DOI] [PubMed] [Google Scholar]

262.Mekinian A., Lazzaroni M.G., Kuzenko A., Alijotas-Reig J., Ruffatti A., Levy P., Canti V., Bremme K., Bezanahary H., Bertero T., et al. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study. Autoimmun. Rev. 2015;14:498–502. doi: 10.1016/j.autrev.2015.01.012. [DOI] [PubMed] [Google Scholar]

263.Mekinian A., Alijotas-Reig J., Carrat F., Costedoat-Chalumeau N., Ruffatti A., Lazzaroni M.G., Tabacco S., Maina A., Masseau A., Morel N., et al. Refractory obstetrical antiphospholipid syndrome: Features, treatment and outcome in a European multicenter retrospective study. Autoimmun. Rev. 2017;16:730–734. doi: 10.1016/j.autrev.2017.05.006. [DOI] [PubMed] [Google Scholar]

264.Ye S.L., Gu X.K., Tao L.Y., Cong J.M., Wang Y.Q. Efficacy of Different Treatment Regimens for Antiphospholipid Syndrome-related Recurrent Spontaneous Abortion. Chin. Med. J. 2017;130:1395–1399. doi: 10.4103/0366-6999.207471. [DOI] [PMC free article] [PubMed] [Google Scholar]

265.Gerde M., Ibarra E., Mac Kenzie R., Fernandez Suarez C., Heer C., Alvarez R., Iglesias M., Balparda J., Beruti E., Rubinstein F. The impact of hydroxychloroquine on obstetric outcomes in refractory obstetric antiphospholipid syndrome. Thromb. Res. 2021;206:104–110. doi: 10.1016/j.thromres.2021.08.004. [DOI] [PubMed] [Google Scholar]

266.Ruffatti A., Tonello M., Hoxha A., Sciascia S., Cuadrado M.J., Latino J.O., Udry S., Reshetnyak T., Costedoat-Chalumeau N., Morel N., et al. Effect of Additional Treatments Combined with Conventional Therapies in Pregnant Patients with High-Risk Antiphospholipid Syndrome: A Multicentre Study. Thromb. Haemost. 2018;47:639–646. doi: 10.1055/s-0038-1632388. [DOI] [PubMed] [Google Scholar]

267.Sciascia S., Hunt B.J., Talavera-Garcia E., Lliso G., Khamashta M.A., Cuadrado M.J. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am. J. Obstet. Gynecol. 2016;214:273.e1–273.e8. doi: 10.1016/j.ajog.2015.09.078. [DOI] [PubMed] [Google Scholar]

268.Sadeghpour S., Ghasemnejad Berenji M., Nazarian H., Ghasemnejad T., Nematollahi M.H., Abroon S., Paktinat S., Heidari Khoei H., Ghasemnejad Berenji H., Ghaffari Novin M. Effects of treatment with hydroxychloroquine on the modulation of Th17/Treg ratio and pregnancy outcomes in women with recurrent implantation failure: Clinical trial. Immunopharmacol. Immunotoxicol. 2020;42:632–642. doi: 10.1080/08923973.2020.1835951. [DOI] [PubMed] [Google Scholar]

269.Dernoncourt A., Hedhli K., Abisror N., Cheloufi M., Cohen J., Kolanska K., McAvoy C., Selleret L., Ballot E., Mathieu d’Argent E., et al. Hydroxychloroquine in recurrent pregnancy loss: Data from a French prospective multicenter registry. Hum. Reprod. 2024;39:1934–1941. doi: 10.1093/humrep/deae146. [DOI] [PMC free article] [PubMed] [Google Scholar]

270.Halloran P.F. Molecular mechanisms of new immunosuppressants. Clin. Transplant. 1996;10:118–123. doi: 10.1111/j.1399-0012.1996.tb00657.x. [DOI] [PubMed] [Google Scholar]

271.Saad A.F., Pacheco L.D., Saade G.R. Immunosuppressant Medications in Pregnancy. Obstet. Gynecol. 2024;143:e94–e106. doi: 10.1097/AOG.0000000000005512. [DOI] [PubMed] [Google Scholar]

272.Cavalcante M.B., Tavares A.C.M., Rocha C.A., de Souza G.F., Lima E.M., Simões J.M.L., de Souza L.C., Martins M.Y.M., de Araújo N.O., Barini R. Calcineurin inhibitors in the management of recurrent miscarriage and recurrent implantation failure: Systematic review and meta-analysis. J. Reprod. Immunol. 2023;160:104157. doi: 10.1016/j.jri.2023.104157. [DOI] [PubMed] [Google Scholar]

273.Nakagawa K., Sugiyama R. Tacrolimus treatment in women with repeated implantation failures. Reprod. Med. Biol. 2024;23:e12558. doi: 10.1002/rmb2.12558. [DOI] [PMC free article] [PubMed] [Google Scholar]

274.Ling Y., Huang Y., Chen C., Mao J., Zhang H. Low dose Cyclosporin A treatment increases live birth rate of unexplained recurrent abortion—Initial cohort study. Clin. Exp. Obstet. Gynecol. 2017;44:230–235. doi: 10.12891/ceog3375.2017. [DOI] [PubMed] [Google Scholar]

275.Azizi R., Ahmadi M., Danaii S., Abdollahi-Fard S., Mosapour P., Eghbal-Fard S., Dolati S., Kamrani A., Rahnama B., Mehdizadeh A., et al. Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1/Th2 ratio. J. Cell. Physiol. 2019;234:19039–19047. doi: 10.1002/jcp.28543. [DOI] [PubMed] [Google Scholar]

276.Fu J.H. Analysis of the use of cyclosporin A to treat refractory immune recurrent spontaneous abortion. Clin. Exp. Obstet. Gynecol. 2015;42:739–742. doi: 10.12891/ceog2006.2015. [DOI] [PubMed] [Google Scholar]

277.Qu D., Tian X., Ding L., Li Y., Zhou W. Impacts of Cyclosporin A on clinical pregnancy outcomes of patients with a history of unexplained transfer failure: A retrospective cohort study. Reprod. Biol Endocrinol. 2021;19:44. doi: 10.1186/s12958-021-00728-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

278.Liu J., Li M., Fu J., Yuan G., Li N., Fu Y., Zhao L. Tacrolimus improved the pregnancy outcomes of patients with refractory recurrent spontaneous abortion and immune bias disorders: A randomized controlled trial. Eur. J. Clin. Pharmacol. 2023;79:627–634. doi: 10.1007/s00228-023-03473-9. [DOI] [PubMed] [Google Scholar]

279.Kuroda K., Ikemoto Y., Horikawa T., Moriyama A., Ojiro Y., Takamizawa S., Uchida T., Nojiri S., Nakagawa K., Sugiyama R. Novel approaches to the management of recurrent pregnancy loss: The OPTIMUM (OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu) treatment strategy. Reprod. Med. Biol. 2021;20:524–536. doi: 10.1002/rmb2.12412. [DOI] [PMC free article] [PubMed] [Google Scholar]

280.Nakagawa K., Kuroda K., Sugiyama R., Yamaguchi K. After 12 consecutive miscarriages, a patient received immunosuppressive treatment and delivered an intact baby. Reprod. Med. Biol. 2017;16:297–301. doi: 10.1002/rmb2.12040. [DOI] [PMC free article] [PubMed] [Google Scholar]

281.Shen P., Zhang T., Han R., Xie H., Lv Q. Co-administration of tacrolimus and low molecular weight heparin in patients with a history of implantation failure and elevated peripheral blood natural killer cell proportion. J. Obstet. Gynaecol. Res. 2022;49:649–657. doi: 10.1111/jog.15500. [DOI] [PubMed] [Google Scholar]

282.Nakagawa K., Kwak-Kim J., Hisano M., Kasahara Y., Kuroda K., Sugiyama R., Yamaguchi K. Obstetric and perinatal outcome of the women with repeated implantation failures or recurrent pregnancy losses who received pre- and post-conception tacrolimus treatment. Am. J. Reprod. Immunol. 2019;82:e13142. doi: 10.1111/aji.13142. [DOI] [PubMed] [Google Scholar]

283.Nakamura A., Tanaka Y., Amano T., Takebayashi A., Takahashi A., Hanada T., Tsuji S., Murakami T. mTOR inhibitors as potential therapeutics for endometriosis: A narrative review. Mol. Hum. Reprod. 2024;30:gaae041. doi: 10.1093/molehr/gaae041. [DOI] [PMC free article] [PubMed] [Google Scholar]

284.Li M.Y., Shen H.H., Cao X.Y., Gao X.X., Xu F.Y., Ha S.Y., Sun J.S., Liu S.P., Xie F., Li M.Q. Targeting a mTOR/autophagy axis: A double-edged sword of rapamycin in spontaneous miscarriage. Biomed. Pharmacother. 2024;177:116976. doi: 10.1016/j.biopha.2024.116976. [DOI] [PubMed] [Google Scholar]

285.Ahmadi M., Abdolmohamadi-Vahid S., Ghaebi M., Dolati S., Abbaspour-Aghdam S., Danaii S., Berjis K., Madadi-Javid R., Nouri Z., Siahmansouri H., et al. Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: A double-blind, phase II randomized clinical trial. Int. Immunopharmacol. 2019;74:105730. doi: 10.1016/j.intimp.2019.105730. [DOI] [PubMed] [Google Scholar]

286.Kwak J.Y.H., Kwak F.M.Y., Ainbinder S.W., Ruiz A.M., Beer A.E. Elevated Peripheral Blood Natural Killer Cells Are Effectively Downregulated by Immunoglobulin G Infusion in Women With Recurrent Spontaneous Abortions. Am. J. Reprod. Immunol. 1996;35:363–369. doi: 10.1111/j.1600-0897.1996.tb00495.x. [DOI] [PubMed] [Google Scholar]

287.Ahmadi M., Abdolmohammadi-Vahid S., Ghaebi M., Aghebati-Maleki L., Afkham A., Danaii S., Abdollahi-Fard S., Heidari L., Jadidi-Niaragh F., Younesi V., et al. Effect of Intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL) Biomed. Pharmacother. 2017;92:1095–1102. doi: 10.1016/j.biopha.2017.06.001. [DOI] [PubMed] [Google Scholar]

288.Ahmadi M., Abdolmohammadi-Vahid S., Ghaebi M., Aghebati-Maleki L., Dolati S., Farzadi L., Ghasemzadeh A., Hamdi K., Younesi V., Nouri M., et al. Regulatory T cells improve pregnancy rate in RIF patients after additional IVIG treatment. Syst. Biol. Reprod. Med. 2017;63:350–359. doi: 10.1080/19396368.2017.1390007. [DOI] [PubMed] [Google Scholar]

289.Yamada H., Deguchi M., Saito S., Takeshita T., Mitsui M., Saito T., Nagamatsu T., Takakuwa K., Nakatsuka M., Yoneda S., et al. High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss. J. Reprod. Immunol. 2023;158:103977. doi: 10.1016/j.jri.2023.103977. [DOI] [PubMed] [Google Scholar]

290.Shi Y., Tan D., Hao B., Zhang X., Geng W., Wang Y., Sun J., Zhao Y. Efficacy of intravenous immunoglobulin in the treatment of recurrent spontaneous abortion: A systematic review and meta-analysis. Am. J. Reprod. Immunol. 2022;88:e13615. doi: 10.1111/aji.13615. [DOI] [PMC free article] [PubMed] [Google Scholar]

291.Christiansen O.B., Kolte A.M., Krog M.C., Nielsen H.S., Egerup P. Treatment with intravenous immunoglobulin in patients with recurrent pregnancy loss: An update. J. Reprod. Immunol. 2019;133:37–42. doi: 10.1016/j.jri.2019.06.001. [DOI] [PubMed] [Google Scholar]

292.Yamada H., Deguchi M., Saito S., Takeshita T., Mitsui M., Saito T. Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial. eClinicalMedicine. 2022;50:101527. doi: 10.1016/j.eclinm.2022.101527. [DOI] [PMC free article] [PubMed] [Google Scholar]

293.Ramos-Medina R., García-Segovia A., Gil J., Carbone J., Aguarón de la Cruz A., Seyfferth A., Alonso B., Alonso J., León J.A., Alecsandru D., et al. Experience in IVIg Therapy for Selected Women with Recurrent Reproductive Failure and NK Cell Expansion. Am. J. Reprod. Immunol. 2014;71:458–466. doi: 10.1111/aji.12217. [DOI] [PubMed] [Google Scholar]

294.Lee S.K., Kim J.Y., Han A.R., Hur S.E., Kim C.J., Kim T.H., Cho B.R., Han J.W., Han S.G., Na B.J., et al. Intravenous Immunoglobulin G Improves Pregnancy Outcome in Women with Recurrent Pregnancy Losses with Cellular Immune Abnormalities. Am J Reprod Immunol. 2016;75:59–68. doi: 10.1111/aji.12442. [DOI] [PubMed] [Google Scholar]

295.Banjar S., Kadour E., Khoudja R., Ton-Leclerc S., Beauchamp C., Beltempo M., Dahan M.H., Gold P., Jacques Kadoch I., Jamal W., et al. Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss. Am. J. Reprod. Immunol. 2023;90:e13737. doi: 10.1111/aji.13737. [DOI] [PubMed] [Google Scholar]

296.Kim J.H., Kim S.H., Yang N., Ko Y., Lee S.R., Chae H.D. Outcomes of Empirical Treatment With Intravenous Immunoglobulin G Combined With Low-Dose Aspirin in Women With Unexplained Recurrent Pregnancy Loss. J. Korean Med. Sci. 2022;37:e200. doi: 10.3346/jkms.2022.37.e200. [DOI] [PMC free article] [PubMed] [Google Scholar]

297.Habets D.H.J., Pelzner K., Wieten L., Spaanderman M.E.A., Villamor E., Al-Nasiry S. Intravenous immunoglobulins improve live birth rate among women with underlying immune conditions and recurrent pregnancy loss: A systematic review and meta-analysis. Allergy Asthma Clin. Immunol. 2022;18:23. doi: 10.1186/s13223-022-00660-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

298.Clark D.A., Coulam C.B., Stricker R.B. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF) J. Assist. Reprod. Genet. 2006;23:1–13. doi: 10.1007/s10815-005-9013-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

299.Kumar P., Philip C.E., Eskandar K., Marron K., Harrity C. Effect of intravenous immunoglobulin therapy in recurrent implantation failure: A Systematic review and meta-analysis. J. Reprod. Immunol. 2024;166:104323. doi: 10.1016/j.jri.2024.104323. [DOI] [PubMed] [Google Scholar]

300.Park J.S., Song A.Y., Bae J.Y., Han J.W., Kim T.H., Kim C.J., Lee S.K. IL-17 Producing T to Foxp3+CD4+ Regulatory T Cell Ratio as a Diagnostic and Prognostic Marker in Women With Recurrent Pregnancy Loss and Its Implications for Intravenous Immunoglobulin Therapy. Am. J. Reprod. Immunol. 2024;92:e70020. doi: 10.1111/aji.70020. [DOI] [PubMed] [Google Scholar]

301.Velikova T., Sekulovski M., Bogdanova S., Vasilev G., Peshevska-Sekulovska M., Miteva D., Georgiev T. Intravenous Immunoglobulins as Immunomodulators in Autoimmune Diseases and Reproductive Medicine. Antibodies. 2023;12:20. doi: 10.3390/antib12010020. [DOI] [PMC free article] [PubMed] [Google Scholar]

302.Perricone R., De Carolis K.B., Greco E., Giacomelli R., Cipriani P., Fontana L., Perricone C. Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion. Rheumatology. 2008;47:646–651. doi: 10.1093/rheumatology/ken046. [DOI] [PubMed] [Google Scholar]

303.Wang S.W., Zhong S.Y., Lou L.J., Hu Z.F., Sun H.Y., Zhu H.Y. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: A meta-analysis. Reprod. BioMed. Online. 2016;33:720–736. doi: 10.1016/j.rbmo.2016.08.025. [DOI] [PubMed] [Google Scholar]

304.Winger E.E., Reed J.L., Ashoush S., El-Toukhy T., Ahuja S., Taranissi M. Elevated Preconception CD56+16+ and/or Th1:Th2 Levels Predict Benefit from IVIG Therapy in Subfertile Women Undergoing IVF. Am. J. Reprod. Immunol. 2011;66:394–403. doi: 10.1111/j.1600-0897.2011.01018.x. [DOI] [PubMed] [Google Scholar]

305.Sung N., Han A.R., Park C.W., Park D.W., Park J.C., Kim N.Y., Lim K.S., Shin J.E., Joo C.W., Lee S.E., et al. Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines. Clin. Exp. Reprod. Med. 2017;44:1–7. doi: 10.5653/cerm.2017.44.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]

306.Woon E.V., Day A., Bracewell-Milnes T., Male V., Johnson M. Immunotherapy to improve pregnancy outcome in women with abnormal natural killer cell levels/activity and recurrent miscarriage or implantation failure: A systematic review and meta-analysis. J. Reprod. Immunol. 2020;142:103189. doi: 10.1016/j.jri.2020.103189. [DOI] [PubMed] [Google Scholar]

307.Porter T.A., Lacoursiere Y., Scott J. Immunotherapy for recurrent miscarriage. Cochrane Database Syst. Rev. 2006:CD000112. doi: 10.1002/14651858.cd000112.pub2. [DOI] [PubMed] [Google Scholar]

308.Urban M.L., Bettiol A., Serena C., Comito C., Turrini I., Fruttuoso S., Silvestri E., Vannacci A., Ravaldi C., Petraglia F., et al. Intravenous immunoglobulin for the secondary prevention of stillbirth in obstetric antiphospholipid syndrome: A case series and systematic review of literature. Autoimmun. Rev. 2020;19:102620. doi: 10.1016/j.autrev.2020.102620. [DOI] [PubMed] [Google Scholar]

309.Perricone R., Di Muzio G., Perricone C., Giacomelli R., De Nardo D., Fontana L., De Carolis C. High Levels of Peripheral Blood NK Cells in Women Suffering from Recurrent Spontaneous Abortion are Reverted from High-Dose Intravenous Immunoglobulins. Am. J. Reprod. Immunol. 2006;55:232–239. doi: 10.1111/j.1600-0897.2005.00356.x. [DOI] [PubMed] [Google Scholar]

310.Elram T., Simon A., Israel S., Revel A., Shveiky D., Laufer N. Treatment of recurrent IVF failure and human leukocyte antigen similarity by intravenous immunoglobulin. Reprod. BioMed. Online. 2005;11:745–749. doi: 10.1016/S1472-6483(10)61694-X. [DOI] [PubMed] [Google Scholar]

311.Rutella S. Granulocyte Colony-Stimulating Factor for the Induction of T-Cell Tolerance. Transplantation. 2007;84((Supplement)):S26–S30. doi: 10.1097/01.tp.0000269611.66517.bf. [DOI] [PubMed] [Google Scholar]

312.Perobelli S.M., Mercadante A.C., Galvani R.G., Gonçalves-Silva T., Alves A.P., Pereira-Neves A., Benchimol M., Nóbrega A., Bonomo A. G-CSF-Induced Suppressor IL-10+ Neutrophils Promote Regulatory T Cells That Inhibit Graft-Versus-Host Disease in a Long-Lasting and Specific Way. J. Immunol. 2016;197:3725–3734. doi: 10.4049/jimmunol.1502023. [DOI] [PubMed] [Google Scholar]

313.Scarpellini F., Sbracia M. Use of granulocyte colony-stimulating factor for the treatment of unexplained recurrent miscarriage: A randomised controlled trial. Hum. Reprod. 2009;24:2703–2708. doi: 10.1093/humrep/dep240. [DOI] [PubMed] [Google Scholar]

314.Eapen A., Joing M., Kwon P., Tong J., Maneta E., Santo C.D., Mussai F., Lissauer D., Carter D., RESPONSE study group et al. Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: A randomized clinical trial. Hum. Reprod. 2019;34:424–432. doi: 10.1093/humrep/dey393. [DOI] [PMC free article] [PubMed] [Google Scholar]

315.Busnelli A., Somigliana E., Cirillo F., Baggiani A., Levi-Setti P.E. Efficacy of therapies and interventions for repeated embryo implantation failure: A systematic review and meta-analysis. Sci. Rep. 2021;11:1747. doi: 10.1038/s41598-021-81439-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

316.Kamath M.S., Chittawar P.B., Kirubakaran R., Mascarenhas M. Use of granulocyte-colony stimulating factor in assisted reproductive technology: A systematic review and meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2017;214:16–24. doi: 10.1016/j.ejogrb.2017.04.022. [DOI] [PubMed] [Google Scholar]

317.Arefi S., Fazeli E., Esfahani M., Borhani N., Yamini N., Hosseini A., Farifteh F. Granulocyte-colony stimulating factor may improve pregnancy outcome in patients with history of unexplained recurrent implantation failure: An RCT. Int. J. Reprod. Biomed. 2018;16:299–304. doi: 10.29252/ijrm.16.5.299. [DOI] [PMC free article] [PubMed] [Google Scholar]

318.Liu M., Yuan Y., Qiao Y., Tang Y., Sui X., Yin P., Yang D. The effectiveness of immunomodulatory therapies for patients with repeated implantation failure: A systematic review and network meta-analysis. Sci. Rep. 2022;12:18434. doi: 10.1038/s41598-022-21014-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

319.Li J., Mo S., Chen Y. The effect of G-CSF on infertile women undergoing IVF treatment: A meta-analysis. Syst. Biol. Reprod. Med. 2017;63:239–247. doi: 10.1080/19396368.2017.1287225. [DOI] [PubMed] [Google Scholar]

320.Fu J., Li L., Qi L., Zhao L. A randomized controlled trial of etanercept in the treatment of refractory recurrent spontaneous abortion with innate immune disorders. Taiwan J. Obstet. Gynecol. 2019;58:621–625. doi: 10.1016/j.tjog.2019.07.007. [DOI] [PubMed] [Google Scholar]

321.Santiago K.Y., Porchia L.M., López-Bayghen E. Endometrial preparation with etanercept increased embryo implantation and live birth rates in women suffering from recurrent implantation failure during IVF. Reprod. Biol. 2021;21:100480. doi: 10.1016/j.repbio.2021.100480. [DOI] [PubMed] [Google Scholar]

322.Winger E.E., Reed J.L. Treatment with Tumor Necrosis Factor Inhibitors and Intravenous Immunoglobulin Improves Live Birth Rates in Women with Recurrent Spontaneous Abortion. Am. J. Reprod. Immunol. 2008;60:8–16. doi: 10.1111/j.1600-0897.2008.00585.x. [DOI] [PubMed] [Google Scholar]

323.Winger E.E., Reed J.L., Ashoush S., Ahuja S., El-Toukhy T., Taranissi M. Treatment with Adalimumab (Humira®) and Intravenous Immunoglobulin Improves Pregnancy Rates in Women Undergoing IVF. Am. J. Reprod. Immunol. 2008;61:113–120. doi: 10.1111/j.1600-0897.2008.00669.x. [DOI] [PubMed] [Google Scholar]

324.Alijotas-Reig J., Esteve-Valverde E., Anunciación-Llunell A., Marques-Soares J., Pardos-Gea J., Miró-Mur F. Pathogenesis, Diagnosis and Management of Obstetric Antiphospholipid Syndrome: A Comprehensive Review. J. Clin. Med. 2022;11:675. doi: 10.3390/jcm11030675. [DOI] [PMC free article] [PubMed] [Google Scholar]

325.Hajipour H., Nejabati H.R., Latifi Z., Hamdi K., Bahrami-Asl Z., Fattahi A., Nouri M. Lymphocytes immunotherapy for preserving pregnancy: Mechanisms and Challenges. Am. J. Reprod. Immunol. 2018;80:e12853. doi: 10.1111/aji.12853. [DOI] [PubMed] [Google Scholar]

326.Yang H., Qiu L., Di W., Zhao A., Chen G., Hu K., Lin Q. Proportional change of CD4+CD25+ regulatory T cells after lymphocyte therapy in unexplained recurrent spontaneous abortion patients. Fertil. Steril. 2009;92:301–305. doi: 10.1016/j.fertnstert.2008.04.068. [DOI] [PubMed] [Google Scholar]

327.Sarkesh A., Sorkhabi A.D., Parhizkar F., Soltani-Zangbar M.S., Yousefi M., Aghebati-Maleki L. The immunomodulatory effect of intradermal allogeneic PBMC therapy in patients with recurrent spontaneous abortion. J. Reprod. Immunol. 2023;156:103818. doi: 10.1016/j.jri.2023.103818. [DOI] [PubMed] [Google Scholar]

328.Liu S., Gu X., Weng R. Clinical effect of lymphocyte immunotherapy on patients with unexplained recurrent spontaneous abortion. Immun. Inflamm. Dis. 2021;9:1272–1278. doi: 10.1002/iid3.474. [DOI] [PMC free article] [PubMed] [Google Scholar]

329.Fainboim L., Belén S., González V., Fernández P. Evaluation of paternal lymphocyte immunotherapy and potential biomarker mixed lymphocyte reaction-blocking factor in an Argentinian cohort of women with unexplained recurrent spontaneous abortion and unexplained infertility. Am. J. Reprod. Immunol. 2021;86:e13422. doi: 10.1111/aji.13422. [DOI] [PubMed] [Google Scholar]

330.Sarno M., Cavalcante M.B., Niag M., Pimentel K., Luz I., Figueiredo B., Michelon T., Neumann J., Lima S., Machado I.N., et al. Gestational and perinatal outcomes in recurrent miscarriages couples treated with lymphocyte immunotherapy. Eur. J. Obstet. Gynecol. Reprod. Biol. X. 2019;3:100036. doi: 10.1016/j.eurox.2019.100036. [DOI] [PMC free article] [PubMed] [Google Scholar]

331.Chen J.L., Yang J.M., Huang Y.Z., Li Y. Clinical observation of lymphocyte active immunotherapy in 380 patients with unexplained recurrent spontaneous abortion. Int. Immunopharmacol. 2016;40:347–350. doi: 10.1016/j.intimp.2016.09.018. [DOI] [PubMed] [Google Scholar]

332.Gharesi-Fard B., Zolghadri J., Foroughinia L., Tavazoo F., Samsami Dehaghani A. Effectiveness of leukocyte immunotherapy in primary recurrent spontaneous abortion (RPL) Iran. J. Immunol. 2007;4:173–178. [PubMed] [Google Scholar]

333.Pandey M.K., Agrawal S. Induction of MLR-Bf and protection of fetal loss: A current double blind randomized trial of paternal lymphocyte immunization for women with recurrent spontaneous abortion. Int. Immunopharmacol. 2004;4:289–298. doi: 10.1016/j.intimp.2004.01.001. [DOI] [PubMed] [Google Scholar]

334.Ober C., Karrison T., Odem R.R., Barnes R.B., Branch D.W., Stephenson M.D., Baron B., Walker M.A., Scott J.R., Schreiber J.R. Mononuclear-cell immunisation in prevention of recurrent miscarriages: A randomised trial. Lancet. 1999;354:365–369. doi: 10.1016/S0140-6736(98)12055-X. [DOI] [PubMed] [Google Scholar]

335.Wong L.F., Porter T.F., Scott J.R. Immunotherapy for recurrent miscarriage. Cochrane Database Syst. Rev. 2014;2014:CD000112. doi: 10.1002/14651858.CD000112.pub3. [DOI] [PMC free article] [PubMed] [Google Scholar]

336.Günther V., Alkatout I., Meyerholz L., Maass N., Görg S., von Otte S., Ziemann M. Live Birth Rates after Active Immunization with Partner Lymphocytes. Biomedicines. 2021;9:1350. doi: 10.3390/biomedicines9101350. [DOI] [PMC free article] [PubMed] [Google Scholar]

337.Liu Z., Xu H., Kang X., Wang T., He L., Zhao A. Allogenic Lymphocyte Immunotherapy for Unexplained Recurrent Spontaneous Abortion: A Meta-Analysis. Am. J. Reprod. Immunol. 2016;76:443–453. doi: 10.1111/aji.12511. [DOI] [PubMed] [Google Scholar]

338.Rasmark Roepke E., Hellgren M., Hjertberg R., Blomqvist L., Matthiesen L., Henic E., Lalitkumar S., Strandell A. Treatment efficacy for idiopathic recurrent pregnancy loss—A systematic review and meta-analyses. Acta Obstet. Gynecol. Scand. 2018;97:921–941. doi: 10.1111/aogs.13352. [DOI] [PubMed] [Google Scholar]

339.Melo P., Thornton T., Coomarasamy A., Granne I. Evidence for the effectiveness of immunologic therapies in women with subfertility and/or undergoing assisted reproduction. Fertil. Steril. 2022;117:1144–1159. doi: 10.1016/j.fertnstert.2022.04.015. [DOI] [PubMed] [Google Scholar]

340.Yu N., Zhang B., Xu M., Wang S., Liu R., Wu J., Yang J., Feng L. Intrauterine administration of autologous peripheral blood mononuclear cells (PBMCs) activated by HCG improves the implantation and pregnancy rates in patients with repeated implantation failure: A prospective randomized study. Am. J. Reprod. Immunol. 2016;76:212–216. doi: 10.1111/aji.12542. [DOI] [PubMed] [Google Scholar]

341.Li S., Wang J., Cheng Y., Zhou D., Yin T., Xu W., Yu N., Yang J. Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J. Reprod. Immunol. 2017;119:15–22. doi: 10.1016/j.jri.2016.11.006. [DOI] [PubMed] [Google Scholar]

342.Maleki-Hajiagha A., Razavi M., Rezaeinejad M., Rouholamin S., Almasi-Hashiani A., Pirjani R., Sepidarkish M. Intrauterine administration of autologous peripheral blood mononuclear cells in patients with recurrent implantation failure: A systematic review and meta-analysis. J. Reprod. Immunol. 2019;131:50–56. doi: 10.1016/j.jri.2019.01.001. [DOI] [PubMed] [Google Scholar]

343.Pourmoghadam Z., Abdolmohammadi-Vahid S., Pashazadeh F., Aghebati-Maleki L., Ansari F., Yousefi M. Efficacy of intrauterine administration of autologous peripheral blood mononuclear cells on the pregnancy outcomes in patients with recurrent implantation failure: A systematic review and meta-analysis. J. Reprod. Immunol. 2020;137:103077. doi: 10.1016/j.jri.2019.103077. [DOI] [PubMed] [Google Scholar]

344.Yakin K., Oktem O. Urman B. Intrauterine administration of peripheral mononuclear cells in recurrent implantation failure: A systematic review and meta-analysis. Sci. Rep. 2019;9:3897. doi: 10.1038/s41598-019-40521-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

345.Cai S., Dai S., Lin R., Huang C., Zeng Y., Diao L., Lian R., Tu W. The effectiveness and safety of intrauterine infusion of autologous regulatory T cells (Tregs) in patients with recurrent pregnancy loss and low levels of endometrial FoxP3+ cells: A retrospective cohort study. Am. J. Reprod. Immunol. 2023;90:e13735. doi: 10.1111/aji.13735. [DOI] [PubMed] [Google Scholar]

346.Ban Y., Yang X., Xing Y., Que W., Yu Z., Gui W., Chen Y., Liu X. Intrauterine Infusion of Leukocyte-Poor Platelet-Rich Plasma Is an Effective Therapeutic Protocol for Patients with Recurrent Implantation Failure: A Retrospective Cohort Study. J. Clin. Med. 2023;12:2823. doi: 10.3390/jcm12082823. [DOI] [PMC free article] [PubMed] [Google Scholar]

347.Kong X., Tang G., Liu Y., Zheng Z., Li Y., Yan F. Efficacy of intrauterine infusion therapy before embryo transfer in recurrent implantation failure: A systematic review and network meta-analysis. J. Reprod. Immunol. 2023;156:103819. doi: 10.1016/j.jri.2023.103819. [DOI] [PubMed] [Google Scholar]

348.Deng H., Wang S., Li Z., Xiao L., Mao Y. Effect of intrauterine infusion of platelet-rich plasma for women with recurrent implantation failure: A systematic review and meta-analysis. J. Obstet. Gynaecol. 2023;43:2144177. doi: 10.1080/01443615.2022.2144177. [DOI] [PubMed] [Google Scholar]

349.Mehrafza M., Pourseify G., Zare Yousefi T., Azadeh R., Saghati Jalali S., Hosseinzadeh E., Samadnia S., Habibdoost M., Tamimi A., Hosseini A. The Efficiency of Introducing Intrauterine Infusion of Autologous Platelet-Rich Plasma versus Granulocyte Colony-Stimulating Factor in Repeated Implantation Failure Patients: An Unblinded Randomised Clinical Trial. Int. J. Fertil. Steril. 2024;18((Suppl. 1)):30–34. doi: 10.22074/ijfs.2024.2013900.1557. [DOI] [PMC free article] [PubMed] [Google Scholar]

350.Kumar P., Marron K., Harrity C. Intralipid therapy and adverse reproductive outcome: Is there any evidence? Reprod. Fertil. 2021;2:173–186. doi: 10.1530/RAF-20-0052. [DOI] [PMC free article] [PubMed] [Google Scholar]

351.Roussev R.G., Acacio B., Ng S.C., Coulam C.B. Duration of Intralipid’s Suppressive Effect on NK Cell’s Functional Activity. Am. J. Reprod. Immunol. 2008;60:258–263. doi: 10.1111/j.1600-0897.2008.00621.x. [DOI] [PubMed] [Google Scholar]

352.Singh N., Davis A.A., Kumar S., Kriplani A. The effect of administration of intravenous intralipid on pregnancy outcomes in women with implantation failure after IVF/ICSI with non-donor oocytes: A randomised controlled trial. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019;240:45–51. doi: 10.1016/j.ejogrb.2019.06.007. [DOI] [PubMed] [Google Scholar]

353.Dakhly D.M.R., Bayoumi Y.A., Sharkawy M., Gad Allah S.H., Hassan M.A., Gouda H.M., Hashem A.T., Hatem D.L., Ahmed M.F., El-Khayat W. Intralipid supplementation in women with recurrent spontaneous abortion and elevated levels of natural killer cells. Int. J. Gynecol. Obstet. 2016;135:324–327. doi: 10.1016/j.ijgo.2016.06.026. [DOI] [PubMed] [Google Scholar]

354.Han E.J., Lee H.N., Kim M.K., Lyu S.W., Lee W.S. Efficacy of intralipid administration to improve in vitro fertilization outcomes: A systematic review and meta-analysis. Clin. Exp. Reprod. Med. 2021;48:203–210. doi: 10.5653/cerm.2020.04266. [DOI] [PMC free article] [PubMed] [Google Scholar]

355.Rimmer M.P., Black N., Keay S., Quenby S., Al Wattar B.H. Intralipid infusion at time of embryo transfer in women with history of recurrent implantation failure: A systematic review and meta-analysis. J. Obstet. Gynaecol. Res. 2021;47:2149–2156. doi: 10.1111/jog.14763. [DOI] [PubMed] [Google Scholar]

356.Marchand G.J., Masoud A.T., Ulibarri H., Arroyo A., Coriell C., Goetz S., Moir C., Moberly A., Gonzalez D., Blanco M., et al. Effect of a 20% intravenous fat emulsion therapy on pregnancy outcomes in women with RPL or RIF undergoing IVF/ICSI: A systematic review and meta-analysis. J. Clin. Transl. Res. 2023;9:236–245. [PMC free article] [PubMed] [Google Scholar]

357.Ndukwe G. Recurrent embryo implantation failure after in vitro fertilisation: Improved outcome following intralipid infusion in women with elevated T Helper 1 response. Hum. Fertil. 2011;14:1–8. [Google Scholar]

358.Coulam C.B. Intralipid treatment for women with reproductive failures. Am. J. Reprod. Immunol. 2021;85:e13290. doi: 10.1111/aji.13290. [DOI] [PubMed] [Google Scholar]

359.Martini A., Jasulaitis S., Fogg L., Uhler M., Hirshfeld-Cytron J. Evaluating the utility of intralipid infusion to improve live birth rates in patients with recurrent pregnancy loss or recurrent implantation failure. J. Hum. Reprod. Sci. 2018;11:261. doi: 10.4103/jhrs.JHRS_28_18. [DOI] [PMC free article] [PubMed] [Google Scholar]

360.Carta G., Iovenitti P., Falciglia K. Recurrent miscarriage associated with antiphospholipid antibodies: Prophylactic treatment with low-dose aspirin and fish oil derivates. Clin. Exp. Obstet. Gynecol. 2005;32:49–51. [PubMed] [Google Scholar]

361.Mu F., Huo H., Wang M., Wang F. Omega-3 fatty acid supplements and recurrent miscarriage: A perspective on potential mechanisms and clinical evidence. Food Sci. Nutr. 2023;11:4460–4471. doi: 10.1002/fsn3.3464. [DOI] [PMC free article] [PubMed] [Google Scholar]

362.Canella P.R.B.C., Vinces S.S., Silva Á.A.R., Sanches P.H.G., Barini R., Porcari A.M., Razolli D.S., Carvalho P.O. Altered profile of plasma phospholipids in woman with recurrent pregnancy loss and recurrent implantation failure treated with lipid emulsion therapy. Am. J. Reprod. Immunol. 2023;89:e13673. doi: 10.1111/aji.13673. [DOI] [PubMed] [Google Scholar]

363.ESHRE Guideline Group on RPL. Bender Atik R., Christiansen O.B., Elson J., Kolte A.M., Lewis S., Middeldorp S., Mcheik S., Peramo B., Quenby S., et al. ESHRE guideline: Recurrent pregnancy loss: An update in 2022. Hum. Reprod. Open. 2023;2023:hoad002. doi: 10.1093/hropen/hoad002. [DOI] [PMC free article] [PubMed] [Google Scholar]

364.Royal College of Obstetricians and Gynaecologists The Investigation and Treatment of Couples with Recurrent First- trimester and Second-trimester Miscarriage Green-top Guideline No. 17. 2022. [(accessed on 8 December 2024)]. Available online: https://www.rcog.org.uk/media/3cbgonl0/gtg_17.pdf.

365.Hamulyák E.N., Scheres L.J., Marijnen M.C., Goddijn M., Middeldorp S. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst. Rev. 2020;5:CD012852. doi: 10.1002/14651858.cd012852.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]

366.Liu X., Qiu Y., Yu E.D., Xiang S., Meng R., Niu K.F., Zhu H. Comparison of therapeutic interventions for recurrent pregnancy loss in association with antiphospholipid syndrome: A systematic review and network meta-analysis. Am. J. Reprod. Immunol. 2020;83:e13219. doi: 10.1111/aji.13219. [DOI] [PubMed] [Google Scholar]

367.Grandone E., Tiscia G.L., Mastroianno M., Larciprete G., Kovač M., Tamborini Permunian E., Lojacono A., Barcellona D., Bitsadze V., Khizroeva J., et al. Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: The OTTILIA registry. Hum. Reprod. 2021;36:2083–2090. doi: 10.1093/humrep/deab153. [DOI] [PubMed] [Google Scholar]

368.Aynıoglu O., Isik H., Sahbaz A., Alptekın H., Bayar U. Does anticoagulant therapy improve adverse pregnancy outcomes in patients with history of recurrent pregnancy loss? Ginekol. Pol. 2016;87:585–591. doi: 10.5603/GP.2016.0049. [DOI] [PubMed] [Google Scholar]

369.Shaaban O.M., Abbas A.M., Zahran K.M., Fathalla M.M., Anan M.A., Salman S.A. Low-Molecular-Weight Heparin for the Treatment of Unexplained Recurrent Miscarriage With Negative Antiphospholipid Antibodies: A Randomized Controlled Trial. Clin. Appl. Thromb. Hemost. 2016;23:567–572. doi: 10.1177/1076029616665167. [DOI] [PubMed] [Google Scholar]

370.Jiang F., Hu X., Jiang K., Pi H., He Q., Chen X. The role of low molecular weight heparin on recurrent pregnancy loss: A systematic review and meta-analysis. Taiwan J. Obstet. Gynecol. 2021;60:1–8. doi: 10.1016/j.tjog.2020.11.001. [DOI] [PubMed] [Google Scholar]

371.Li J., Gao Y.H., Xu L., Li Z.Y. Meta-analysis of heparin combined with aspirin versus aspirin alone for unexplained recurrent spontaneous abortion. Int. J. Gynaecol. Obstet. 2020;151:23–32. doi: 10.1002/ijgo.13266. [DOI] [PubMed] [Google Scholar]

372.Skeith L., Carrier M., Kaaja R., Martinelli I., Petroff D., Schleußner E., Laskin C.A., Rodger M.A. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood. 2016;127:1650–1655. doi: 10.1182/blood-2015-12-626739. [DOI] [PubMed] [Google Scholar]

373.de Jong P., Kaandorp S., Di Nisio M., Goddijn M., Middeldorp S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst. Rev. 2014;2014:CD004734. doi: 10.1002/14651858.CD004734.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]

374.Schleussner E., Kamin G., Seliger G., Rogenhofer N., Ebner S., Toth B., Schenk M., Henes M., Bohlmann M.K., Fischer T., et al. Low-Molecular-Weight Heparin for Women With Unexplained Recurrent Pregnancy Loss. Ann. Intern. Med. 2015;162:601–609. doi: 10.7326/M14-2062. [DOI] [PubMed] [Google Scholar]

375.Karadağ C., Akar B., Gönenç G., Aslancan R., Yılmaz N., Çalışkan E. Aspirin, low molecular weight heparin, or both in preventing pregnancy complications in women with recurrent pregnancy loss and factor V Leiden mutation. J. Matern.-Fetal Neonatal Med. 2020;33:1934–1939. doi: 10.1080/14767058.2019.1671348. [DOI] [PubMed] [Google Scholar]

376.Lin T., Chen Y., Cheng X., Li N., Sheng X. Enoxaparin (or plus aspirin) for the prevention of recurrent miscarriage: A meta-analysis of randomized controlled studies. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019;234:53–57. doi: 10.1016/j.ejogrb.2018.12.023. [DOI] [PubMed] [Google Scholar]

377.Wang G., Zhang R., Li C., Chen A. Evaluation of the effect of low molecular weight heparin in unexplained recurrent pregnancy loss: A meta-analysis of randomized controlled trials. J. Matern.-Fetal Neonatal Med. 2021;35:7601–7608. doi: 10.1080/14767058.2021.1957819. [DOI] [PubMed] [Google Scholar]

378.Scarrone M., Salmeri N., Buzzaccarini G., Canti V., Pasi F., Papaleo E., Rovere-Querini P., Candiani M., Alteri A., Busnelli A., et al. Low-molecular-weight heparin in the prevention of unexplained recurrent miscarriage: A systematic review and meta-analysis. Sci. Rep. 2024;14:14168. doi: 10.1038/s41598-024-62949-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

379.Scarrone M., Canti V., Vanni V.S., Bordoli S., Pasi F., Quaranta L., Erra R., De Lorenzo R., Rosa S., Castiglioni M.T., et al. Treating unexplained recurrent pregnancy loss based on lessons learned from obstetric antiphospholipid syndrome and inherited thrombophilia: A propensity-score adjusted retrospective study. J. Reprod. Immunol. 2022;154:103760. doi: 10.1016/j.jri.2022.103760. [DOI] [PubMed] [Google Scholar]

380.Quenby S., Booth K., Hiller L., Coomarasamy A., de Jong P.G., Hamulyák E.N., Scheres L.J., van Haaps T.F., Ewington L., Tewary S., et al. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): An international open-label, randomised controlled trial. Lancet. 2023;402:54–61. doi: 10.1016/S0140-6736(23)00693-1. [DOI] [PubMed] [Google Scholar]

381.Giouleka S., Tsakiridis I., Arsenaki E., Kalogiannidis I., Mamopoulos A., Papanikolaou E., Athanasiadis A., Dagklis T. Investigation and Management of Recurrent Pregnancy Loss: A Comprehensive Review of Guidelines. Obstet. Gynecol. Surv. 2023;78:287–301. doi: 10.1097/OGX.0000000000001133. [DOI] [PubMed] [Google Scholar]

382.Kuroda K., Matsumura Y., Ikemoto Y., Segawa T., Hashimoto T., Fukuda J., Nakagawa K., Uchida T., Ochiai A., Horimoto Y., et al. Analysis of the risk factors and treatment for repeated implantation failure: OPtimization of Thyroid function, IMmunity, and Uterine Milieu (OPTIMUM) treatment strategy. Am. J. Reprod. Immunol. 2021;85:e13376. doi: 10.1111/aji.13376. [DOI] [PubMed] [Google Scholar]

383.Kuroda K., Horikawa T., Moriyama A., Ojiro Y., Takamizawa S., Watanabe H., Maruyama T., Nojiri S., Nakagawa K., Sugiyama R. Therapeutic efficacy of the optimization of thyroid function, thrombophilia, immunity and uterine milieu (OPTIMUM) treatment strategy on pregnancy outcomes after single euploid blastocyst transfer in advanced age women with recurrent reproductive failure. Reprod. Med. Biol. 2023;22:e12554. doi: 10.1002/rmb2.12554. [DOI] [PMC free article] [PubMed] [Google Scholar]

384.Mohammad-Akbari A., Mohazzab A., Tavakoli M., Karimi A., Zafardoust S., Zolghadri Z., Shahali S., Tokhmechi R., Ansaripour S. The effect of low-molecular-weight heparin on live birth rate of patients with unexplained early recurrent pregnancy loss: A two-arm randomized clinical trial. J. Res. Med. Sci. 2022;27:78. doi: 10.4103/jrms.jrms_81_21. [DOI] [PMC free article] [PubMed] [Google Scholar]

385.Dolitzky M., Inbal A., Segal Y., Weiss A., Brenner B., Carp H. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil. Steril. 2006;86:362–366. doi: 10.1016/j.fertnstert.2005.12.068. [DOI] [PubMed] [Google Scholar]

386.Naimi A.I., Perkins N.J., Sjaarda L.A., Mumford S.L., Platt R.W., Silver R.M., Schisterman E.F. The Effect of Preconception-Initiated Low-Dose Aspirin on Human Chorionic Gonadotropin-Detected Pregnancy, Pregnancy Loss, and Live Birth: Per Protocol Analysis of a Randomized Trial. Ann. Intern. Med. 2021;174:595–601. doi: 10.7326/M20-0469. [DOI] [PMC free article] [PubMed] [Google Scholar]

387.Mumford S.L., Silver R.M., Sjaarda L.A., Wactawski-Wende J., Townsend J.M., Lynch A.M., Galai N., Lesher L.L., Faraggi D., Perkins N.J., et al. Expanded findings from a randomized controlled trial of preconception low-dose aspirin and pregnancy loss. Hum. Reprod. 2016;31:657–665. doi: 10.1093/humrep/dev329. [DOI] [PMC free article] [PubMed] [Google Scholar]

388.Blomqvist L., Hellgren M., Strandell A. Acetylsalicylic acid does not prevent first-trimester unexplained recurrent pregnancy loss: A randomized controlled trial. Acta Obstet. Gynecol. Scand. 2018;97:1365–1372. doi: 10.1111/aogs.13420. [DOI] [PubMed] [Google Scholar]

389.Ikemoto Y., Kuroda K., Nakagawa K., Ochiai A., Ozaki R., Murakami K., Jinushi M., Matsumoto A., Sugiyama R., Takeda S. Vitamin D Regulates Maternal T-Helper Cytokine Production in Infertile Women. Nutrients. 2018;10:902. doi: 10.3390/nu10070902. [DOI] [PMC free article] [PubMed] [Google Scholar]

390.Ota K., Dambaeva S., Kim M.W., Han A.R., Fukui A., Gilman-Sachs A., Beaman K., Kwak-Kim J. 1,25-Dihydroxy-vitamin D3 regulates NK-cell cytotoxicity, cytokine secretion, and degranulation in women with recurrent pregnancy losses. Eur. J. Immunol. 2015;45:3188–3199. doi: 10.1002/eji.201545541. [DOI] [PubMed] [Google Scholar]

391.Ichikawa T., Toyoshima M., Watanabe T., Negishi Y., Kuwabara Y., Takeshita T., Suzuki S. Associations of Nutrients and Dietary Preferences with Recurrent Pregnancy Loss and Infertility. J. Nippon Med. Sch. 2024;91:254–260. doi: 10.1272/jnms.JNMS.2024_91-313. [DOI] [PubMed] [Google Scholar]

392.Chen X., Yin B., Lian R.C., Zhang T., Zhang H.Z., Diao L.H., Li Y.Y., Huang C.Y., Liang D.S., Zeng Y. Modulatory effects of vitamin D on peripheral cellular immunity in patients with recurrent miscarriage. Am. J. Reprod. Immunol. 2016;76:432–438. doi: 10.1111/aji.12585. [DOI] [PubMed] [Google Scholar]

393.Tamblyn J.A., Pilarski N.S.P., Markland A.D., Marson E.J., Devall A., Hewison M., Morris R.K., Coomarasamy A. Vitamin D and miscarriage: A systematic review and meta-analysis. Fertil. Steril. 2022;118:111–122. doi: 10.1016/j.fertnstert.2022.04.017. [DOI] [PubMed] [Google Scholar]

394.Raghupathy R., Szekeres-Bartho J. Progesterone: A Unique Hormone with Immunomodulatory Roles in Pregnancy. Int. J. Mol. Sci. 2022;23:1333. doi: 10.3390/ijms23031333. [DOI] [PMC free article] [PubMed] [Google Scholar]

395.Lee J.H., Lydon J.P., Kim C.H. Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability. Eur. J. Immunol. 2012;42:2683–2696. doi: 10.1002/eji.201142317. [DOI] [PMC free article] [PubMed] [Google Scholar]

396.Green E.S., Moldenhauer L.M., Groome H.M., Sharkey D.J., Chin P.Y., Care A.S., Robker R.L., McColl S.R., Robertson S.A. Regulatory T cells are paramount effectors in progesterone regulation of embryo implantation and fetal growth. JCI Insight. 2023;8:e162995. doi: 10.1172/jci.insight.162995. [DOI] [PMC free article] [PubMed] [Google Scholar]

397.Haas D.M., Hathaway T.J., Ramsey P.S. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst. Rev. 2019;2019:CD003511. doi: 10.1002/14651858.CD003511.pub5. [DOI] [PMC free article] [PubMed] [Google Scholar]

398.Devall A.J., Papadopoulou A., Haas D.M., Price M.J., Coomarasamy A., Gallos I.D. Progestogens for preventing miscarriage: A network meta-analysis. Cochrane Database Syst. Rev. 2021;4:CD013792. doi: 10.1002/14651858.cd013792. [DOI] [PMC free article] [PubMed] [Google Scholar]

399.Zhao Y., D’Souza R., Gao Y., Hao Q., Kallas-Silva L., Steen J.P., Guyatt G. Progestogens in women with threatened miscarriage or recurrent miscarriage: A meta-analysis. Acta Obstet. Gynecol. Scand. 2024;103:1689–1701. doi: 10.1111/aogs.14829. [DOI] [PMC free article] [PubMed] [Google Scholar]

400.Xie H., Zeng H., He D., Liu N. Effect of intrauterine perfusion of human chorionic gonadotropin before embryo transfer after two or more implantation failures: A systematic review and meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019;243:133–138. doi: 10.1016/j.ejogrb.2019.10.039. [DOI] [PubMed] [Google Scholar]

401.Bakry M.S., Eldesouky E., Alghazaly M.M., Farag E., Sultan E.E.K., Elazzazy H., Mohamed A., Ali S.M.S., Anwar A., Elrashedy A.A., et al. Granulocyte colony stimulating factor versus human chorionic gonadotropin for recurrent implantation failure in intra cytoplasmic sperm injection: A randomized clinical trial. BMC Pregnancy Childbirth. 2022;22:881. doi: 10.1186/s12884-022-05098-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

402.Amooee S., Shomali Z., Namazi N., Jannati F. Is There any Role for Granulocyte Colony Stimulating Factor in Improvement of Implantation in Intrauterine Insemination? A Prospective Double-Blind Randomized Control Trial. Int. J. Fertil. Steril. 2022;16:281–285. doi: 10.22074/ijfs.2021.537125.1171. [DOI] [PMC free article] [PubMed] [Google Scholar]

403.Bellver J., Marín C., Lathi R.B., Murugappan G., Labarta E., Vidal C., Giles J., Cabanillas S., Marzal A., Galliano D., et al. Obesity Affects Endometrial Receptivity by Displacing the Window of Implantation. Reprod. Sci. 2021;28:3171–3180. doi: 10.1007/s43032-021-00631-1. [DOI] [PubMed] [Google Scholar]

404.Gonnella F., Konstantinidou F., Donato M., Gatta D.M.P., Peserico A., Barboni B., Stuppia L., Nothnick W.B., Gatta V. The Molecular Link between Obesity and the Endometrial Environment: A Starting Point for Female Infertility. Int. J. Mol. Sci. 2024;25:6855. doi: 10.3390/ijms25136855. [DOI] [PMC free article] [PubMed] [Google Scholar]

405.Gonçalves C.C.R.A., Feitosa B.M., Cavalcante B.V., Lima A.L.G.S.B., de Souza C.M., Joventino L.B., Cavalcante M.B. Obesity and recurrent miscarriage: The interconnections between adipose tissue and the immune system. Am. J. Reprod. Immunol. 2023;90:e13757. doi: 10.1111/aji.13757. [DOI] [PubMed] [Google Scholar]

406.Ramidi G., Khan N., Glueck C.J., Wang P., Goldenberg N. Enoxaparin-metformin and enoxaparin alone may safely reduce pregnancy loss. Trans. Res. J. Lab. Clin. Med. 2009;153:33–43. doi: 10.1016/j.trsl.2008.11.003. [DOI] [PubMed] [Google Scholar]

407.Silverii G.A. Optimizing metformin therapy in practice: Tailoring therapy in specific patient groups to improve tolerability, efficacy and outcomes. Diabetes Obes. Metab. 2024;26((Suppl. 3)):42–54. doi: 10.1111/dom.15749. [DOI] [PubMed] [Google Scholar]

408.Rajeev D., MacIver N.J. Metformin as a Therapeutic Agent for Obesity-Associated Immune Dysfunction. J. Nutr. 2024;154:2534–2542. doi: 10.1016/j.tjnut.2024.07.001. [DOI] [PubMed] [Google Scholar]

409.Sola-Leyva A., Pathare A.D.S., Apostolov A., Aleksejeva E., Kask K., Tammiste T., Ruiz-Durán S., Risal S., Acharya G., Salumets A. The hidden impact of GLP-1 receptor agonists on endometrial receptivity and implantation. Acta Obstet. Gynecol. Scand. 2024 doi: 10.1111/aogs.15010. [DOI] [PMC free article] [PubMed] [Google Scholar]

410.Maslin K., Alkutbe R., Gilbert J., Pinkney J., Shawe J. What is known about the use of weight loss medication in women with overweight/obesity on fertility and reproductive health outcomes? A scoping review. Clin. Obes. 2024;14:e12690. doi: 10.1111/cob.12690. [DOI] [PubMed] [Google Scholar]

411.Dang D., Dearholt S., Bissett K., Ascenzi J., Whalen M. Johns Hopkins Evidence-Based Practice for Nurses and Healthcare Professionals: Model and Guidelines. 4th ed. Sigma Theta Tau International; Indianapolis, IN, USA: 2022. [Google Scholar]

上一篇：人工智能预测冠状动脉搭桥术后新发房颤的性能

下一篇：没有了！