發(fā)布時間： 2025-03-17 15:18:56
反復(fù)妊娠丟失（recurrent pregnancy loss, RPL）定義為連續(xù)發(fā)生兩次或兩次以上的妊娠丟失。約一半病例沒有明確病因，被稱為不明原因反復(fù)妊娠丟失（unexplained recurrent pregnancy loss，URPL）。母胎免疫功能失調(diào)被認為是URPL的病因之一。人類白細胞抗原相容性增加、易感基因、缺乏阻斷抗體以及免疫細胞功能失調(diào)都會破壞母胎界面的免疫耐受環(huán)境。為了糾正母胎免疫失衡，一些免疫療法已被用于URPL治療。本綜述總結(jié)了URPL患者母胎界面免疫微環(huán)境的特點和機制，以及相關(guān)免疫療法，為今后的研究提供參考。
反復(fù)妊娠丟失（recurrent pregnancy loss, RPL）是一種常見的妊娠早期并發(fā)癥，以連續(xù)多次自然流產(chǎn)為特點。美國生殖醫(yī)學(xué)會（ASRM）將其定義為兩次或兩次以上臨床妊娠丟失，但不強調(diào)流產(chǎn)的連續(xù)性和孕齡[1]。歐洲人類生殖與胚胎學(xué)學(xué)會（ESHRE）將其定義為連續(xù)發(fā)生兩次及以上在妊娠24周前的胎兒丟失[2]?？傊?，RPL的定義尚未統(tǒng)一。關(guān)于流產(chǎn)的孕齡、連續(xù)性、配偶的同一性以及是否包括生化妊娠仍存爭議。
RPL給渴望生育的夫婦帶來了巨大的心理壓力和經(jīng)濟負擔。近年來，RPL的發(fā)病率逐年上升，全球約有1%-2%的夫婦受到影響[2]。染色體異常是流產(chǎn)的常見原因。此外，子宮解剖結(jié)構(gòu)異常、內(nèi)分泌失調(diào)、病毒感染、慢性疾病、有害環(huán)境暴露，甚至孕婦年齡增加等因素都會增加RPL的風險[3]。然而，經(jīng)過綜合評估后，仍有約一半的RPL病例原因不明，被稱為不明原因RPL（unexplained recurrent pregnancy loss，URPL），母胎免疫功能失調(diào)可能是URPL的主要機制[4, 5]。
對母體而言，胎兒被視為半異體移植，因此母胎界面的免疫耐受對維持妊娠至關(guān)重要[6]。URPL患者存在明顯的母胎免疫功能障礙，包括阻斷抗體缺乏、免疫細胞異常、細胞因子分泌紊亂、人類白細胞抗原（human leukocyte antigen，HLA）表達異常等[7, 8]。近年來，出現(xiàn)了一些針對URPL的免疫療法，并呈現(xiàn)出不同的臨床表現(xiàn)[9]。本綜述以“不明原因的復(fù)發(fā)性妊娠丟失”、“母胎免疫耐受”和“免疫療法”為主要關(guān)鍵詞，系統(tǒng)檢索和整理了截至2024年11月1日在PubMed和Web of Science上的所有相關(guān)英文文獻。本研究旨在總結(jié)URPL母胎免疫調(diào)節(jié)失調(diào)機制的研究進展，以及URPL的潛在免疫療法。
早期研究認為，持續(xù)的免疫抑制是成功妊娠的重要條件。然而，后續(xù)研究發(fā)現(xiàn)，免疫缺陷和蛻膜內(nèi)免疫細胞缺乏會影響胚胎著床和胎盤發(fā)育[6]。除了蛻膜基質(zhì)細胞和滋養(yǎng)層細胞，免疫細胞浸潤也是母胎界面微環(huán)境的重要組成部分。子宮內(nèi)膜蛻膜化為胚胎著床提供了適宜的環(huán)境，隨后胎兒絨毛外滋養(yǎng)層細胞（extravillous trophoblasts，EVTs）侵入子宮，將螺旋動脈重塑為擴張的大血管[10]。在這一過程中，免疫細胞也發(fā)揮了重要作用。蛻膜自然殺傷細胞（decidual natural killer，dNK）通過分解平滑肌和分泌趨化因子吸引入侵的EVTs，促進螺旋動脈重塑；蛻膜巨噬細胞則負責清除這一過程中產(chǎn)生的凋亡碎片[11]。此后，在妊娠期類固醇激素的影響下，蛻膜組織中的免疫細胞亞群及其分泌的細胞因子發(fā)生了一系列生理變化，形成了一個獨特的母胎免疫微環(huán)境。
妊娠早期，子宮內(nèi)膜基質(zhì)細胞和浸潤的免疫細胞在著床部位分泌多種炎癥因子，包括白細胞介素-6、白細胞介素-8、腫瘤壞死因子α和趨化因子配體1（CXCL1）[12]。子宮內(nèi)膜活檢可誘導(dǎo)炎癥反應(yīng)。研究發(fā)現(xiàn)，活檢增加了子宮內(nèi)膜容受性，提示免疫浸潤形成的炎癥環(huán)境是妊娠早期胚胎著床和胎盤形成的重要條件[13]。
胎盤形成后，不同表型和功能的免疫細胞在母胎界面共同建立免疫耐受微環(huán)境。其中，蛻膜巨噬細胞主要呈現(xiàn)M2抗炎表型，促進滋養(yǎng)層細胞侵襲和胎兒組織更新。同時吞噬衰老凋亡的滋養(yǎng)層細胞，以防止父系抗原暴露引發(fā)的胎兒免疫反應(yīng)。dNK細胞主要表現(xiàn)為CD56+CD16-表型，細胞毒性較低，通過與CD14+巨噬細胞相互作用，誘導(dǎo)調(diào)節(jié)性T（Treg）細胞生成，進而抑制免疫反應(yīng)[15]。此外，Tregs還可調(diào)節(jié)Th17細胞的數(shù)量和功能，發(fā)揮抗炎作用[16]。
臨產(chǎn)前，胎盤界面的免疫環(huán)境再次發(fā)生變化。免疫細胞向子宮肌層浸潤，有助于促進子宮收縮、分娩和胎盤剝離，這些是分娩做準備的生理過程。促炎性核因子-κB（NF-κB）信號通路是啟動分娩和在分娩過程中持續(xù)發(fā)揮作用的途徑[17]。研究發(fā)現(xiàn)，在羊膜腔內(nèi)注射NF-κB抑制肽SN50可推遲懷孕大鼠的分娩時間[18]。一項單細胞RNA測序研究發(fā)現(xiàn)，胎兒間充質(zhì)細胞和母體蛻膜細胞在炎癥信號釋放中尤為活躍。CXCL、TNF、galectins和IL-6等炎癥通路均參與了分娩過程[19]。
主要組織相容性復(fù)合體（major histocompatibility complex, MHC）分子是高度多態(tài)的蛋白質(zhì)，主要功能是向抗原特異性T細胞呈遞抗原肽[20]。人類MHC分子被稱為HLA，分為三類。在正常妊娠期間，父母雙方的HLA是不相容的。胚胎攜帶的父親HLA會刺激母親免疫系統(tǒng)產(chǎn)生抗體，從而誘導(dǎo)母胎免疫耐受維持妊娠。EVTs不表達移植過程中同種異體T細胞的主要靶標，包括HLA-A、HLA-B、HLA-DR、HLA-DQ和HLA-DP分子等，反而表達HLA-C、HLA-E、HLA-F和HLA-G分子[20]。
HLA-C分為HLA-C1和HLA-C2兩類。殺傷免疫球蛋白樣受體（Killer Immunoglobulin-like Receptor，KIR）是HLA-C的受體，主要表達于NK細胞表面[21]。KIR有兩種亞型，一個具有激活功能，一個具有抑制功能。HLA-C與NK細胞上的抑制性KIR相互作用可抑制NK細胞的殺傷活性，從而促進EVTs侵襲和胎盤血管重塑[22]。Sharkey等發(fā)現(xiàn)，妊娠早期蛻膜組織中表達KIRs的CD56+細胞比例增加，且KIR基因的mRNA表達水平升高[23]。此外，部分蛻膜T細胞亞群表達靶向HLA-C的KIRs[24]。研究表明，T細胞上的KIR受體可抑制TCR介導(dǎo)的活化，并影響其在細胞毒性和細胞因子產(chǎn)生中的作用[20]。
吸收其他HLA I類分子前導(dǎo)序列的肽段，可調(diào)節(jié)HLA-E在細胞表面的表達[22]。HLA-E是NK細胞上抑制性受體CD94/NKG2A復(fù)合物的主要配體。若缺乏源自HLA-I分子的肽段，HLA-E無法呈現(xiàn)至細胞表面，導(dǎo)致細胞更易遭受NK細胞誘導(dǎo)的細胞毒性的影響。此外，HLA-E與CD8+ T細胞上的受體CD94/NKG2C結(jié)合，可激活CD8+ T細胞亞群增殖及其功能啟動[25]。
HLA-F是一種非經(jīng)典HLA I類分子，多態(tài)性有限，在各種細胞類型中普遍表達。激活dNK細胞上的KIR2DS4，可分泌粒細胞巨噬細胞集落刺激因子等趨化因子，從而促進滋養(yǎng)層細胞侵襲。因此，滋養(yǎng)層細胞中HLA-F表達水平升高，可能是dNK細胞支持胚胎著床的關(guān)鍵機制[26]。
HLA-G是一種低多態(tài)性的非經(jīng)典MHC I類分子，特異性表達于EVTs表面，對建立母胎免疫耐受和維持正常妊娠至關(guān)重要。HLA-G與dNK細胞表面的KIR2DL4受體結(jié)合后，可上調(diào)CXCL10、胎盤生長因子和血管內(nèi)皮生長因子，促進血管重塑[27]。此外，ILT2與蛻膜樹突狀細胞（dDCs）上的HLA-G結(jié)合時，可上調(diào)IL-10和IL-6表達，抑制異體淋巴細胞增殖，促使dDCs分化為耐受性表型[28]。
在正常妊娠中，足月孕婦血清中的阻斷因子可阻斷父系抗原誘導(dǎo)的母體淋巴細胞增殖20]。這些阻斷因子的主要成分是IgG。阻斷抗體（又稱抗父系淋巴細胞抗體）在妊娠早期開始產(chǎn)生，妊娠頭三個月達峰，隨后逐漸下降，分娩時再次上升，并隨著妊娠次數(shù)的增加而增加[29]。研究發(fā)現(xiàn)，阻斷抗體不僅能覆蓋父系異體抗原，阻止免疫識別，還能降低外周血NK細胞比例，推動免疫平衡從Th1型向Th2型偏移[7]。
母胎免疫耐受是成功妊娠的必要條件。在孕早期，蛻膜中含有大量NK細胞，占比>70%，其次是蛻膜巨噬細胞，約占20%-25%。此外，各種T細胞和樹突狀細胞也參與了蛻膜免疫微環(huán)境的形成[10]。
根據(jù)分布情況，NK細胞可分為外周NK細胞、dNK細胞和子宮NK細胞。其中，dNK細胞表達一系列特異性識別滋養(yǎng)層細胞表面HLA抗原的受體（如KIR識別HLA-C，CD94/NKG2A識別HLA-E，ILT2識別HLA-G）[14]。EVTs已被證實可以通過其表面的HLA-G分子與dNK細胞上的抑制性受體（KIR2DL4和LILRB）相互作用，從而避免被NK細胞溶解[16]。此外，根據(jù)細胞表面標志物的表達，dNK細胞可進一步分為兩個亞群：CD56bright CD16- dNK1細胞細胞毒性低，分泌血管內(nèi)皮生長因子和生長促進因子，促進胎盤發(fā)育和胎兒生長；CD56dim CD16+ dNK2細胞分泌多種促炎細胞因子，細胞毒性高，負責檢測和抗感染[30]。由dNK1亞型主導(dǎo)的蛻膜環(huán)境，對維持母胎界面免疫相容性至關(guān)重要[31]。
在對各種信號和刺激做出反應(yīng)時，巨噬細胞會表現(xiàn)出兩種極化形式，即M1和M2，每種極化形式都具有獨特的生物學(xué)作用。M1巨噬細胞分泌促炎細胞因子，包括IL-1β、IL-6和TNF-α，在調(diào)節(jié)免疫反應(yīng)以對抗感染方面發(fā)揮著重要作用，但也會導(dǎo)致組織損傷。相反，M2巨噬細胞會產(chǎn)生抗炎細胞因子，包括IL-10和轉(zhuǎn)化生長因子β（TGF-β）。在孕早期，蛻膜巨噬細胞主要是免疫抑制型的M2表型[16]，參與蛻膜重塑、滋養(yǎng)層細胞浸潤、血管生成和抑制T細胞活化，對維持免疫平衡和防止過度炎癥反應(yīng)至關(guān)重要。
滋養(yǎng)層細胞參與蛻膜巨噬細胞的招募和分化。滋養(yǎng)層細胞通過分泌巨噬細胞集落刺激因子（M-CSF）和IL-10，誘導(dǎo)招募的CD14+單核細胞分化成M2表型[6]。這些巨噬細胞可清除凋亡的滋養(yǎng)層細胞碎片來抑制炎癥通路的激活，還會產(chǎn)生吲哚胺2,3-雙加氧酶，導(dǎo)致色氨酸降解并抑制T細胞活化[32]。
T細胞是適應(yīng)性免疫中不可或缺的白細胞，可以分化成Th1、Th2、Th17、Treg細胞等多種亞群。
Th2型細胞因子（如IL-4、IL-5和IL-10）在母胎界面產(chǎn)生，通過調(diào)節(jié)免疫反應(yīng)促進胎兒生長和著床，從而維持妊娠。相反，Th1型細胞因子，包括IFN-γ、IL-2和TNF-α，會引發(fā)胎兒排斥反應(yīng)，并阻礙滋養(yǎng)層細胞的增殖和分化，不利于成功妊娠。正常蛻膜免疫結(jié)構(gòu)的特點是Th1/Th2平衡向Th2型偏移[10]。
Th17細胞主要分泌IL-17，在妊娠期參與針對胞外病原體的防御性免疫反應(yīng)。然而，Th17介導(dǎo)的免疫過度會導(dǎo)致中性粒細胞在母胎界面肆意浸潤[33]。Treg細胞分泌與免疫耐受相關(guān)的細胞因子，并抑制Th17細胞的過度激活，從而誘導(dǎo)母胎免疫耐受[3]。研究證實，健康妊娠胎盤界面上Th1/Th2和Th17/Treg的比例較低，Th2和Treg細胞分泌的IL-10和TGF-β等細胞因子可誘導(dǎo)母胎界面形成免疫耐受[34]。
雖然臨床上并未推薦對URPL患者進行HLA、阻斷抗體和免疫細胞等免疫學(xué)檢測[35, 36]，但大量研究證明它們參與了URPL的發(fā)病。本節(jié)將討論這些母胎界面免疫變化的最新研究成果。
目前，MHC和易感基因理論被認為可以部分解釋URPL的發(fā)病機制。配偶間HLA基因位點相容性增加可能導(dǎo)致阻斷抗體無法產(chǎn)生。臨床研究發(fā)現(xiàn)，共享兩個或以上HLA等位基因的夫婦，RPL風險升高[37]。一項薈萃分析表明，雖然RPL夫婦與對照夫婦在HLA-A、-B和-C位點的等位基因共享方面無顯著差異，但RPL夫婦在HLA-DR位點的等位基因共享顯著增加，表明HLA-DR相容性與RPL風險之間存在潛在關(guān)聯(lián)[38]。
此外，母體易感基因位點可能導(dǎo)致對胚胎抗原的免疫反應(yīng)不足。在一項涉及高加索人群的病例對照研究中，HLA-DRB1*03被確定為RPL的易感等位基因[39]。在臺灣人群中，HLA-DRB1*07和HLA-B13的頻率較高[37]。HLA DQ2/DQ8的表達可影響子宮內(nèi)膜微生物群組成，增加了RPL患者患乳糜瀉的易感性[40-42]。最近的一項大規(guī)模GWAS分析探討了全基因組罕見拷貝數(shù)變異對URPL易感性的影響[43]，發(fā)現(xiàn)HLA-C變異與URPL風險的關(guān)系最為顯著。單倍型HLA-C*12:02、HLA-B*52:01和HLA-DRB1*15:02具有明顯的保護作用。然而，cadherin11基因罕見功能缺失變異與URPL風險有關(guān)。
除MHC和易感基因理論外，HLA-C/HLA-G與RPL的關(guān)聯(lián)也在研究中[7]。HLA-C2與抑制性KIR的匹配，以及HLA-G基因14 bp插入可能與URPL有關(guān)[44，45]。然而，HLA多態(tài)性與RPL患者妊娠結(jié)局的關(guān)聯(lián)仍未充分探究。目前，僅推薦對生育男嬰后出現(xiàn)繼發(fā)性RPL的北歐婦女，進行HLA II類分型（HLA-DRB1*15:01、HLA-DRB1*07和HLA-DQB1*05:01/05:2），以評估預(yù)后[35]。
一項研究顯示，成功妊娠的RPL婦女中阻斷抗體陽性率（82.4%）明顯高于流產(chǎn)組（10%）。母體混合淋巴細胞反應(yīng)（MLR）阻斷因子因針對精子中滋養(yǎng)層-淋巴細胞交叉反應(yīng)抗原（TLX）而產(chǎn)生，與HLA分子和滋養(yǎng)層抗原具有交叉反應(yīng)性，附著于滋養(yǎng)層細胞上的Fc片段受體，可保護胚胎免受免疫攻擊[8]。此外，研究發(fā)現(xiàn)MLR阻斷抗體主要屬于免疫球蛋白G-3亞類，在妊娠期間自然產(chǎn)生，也可通過RPL婦女的免疫治療誘導(dǎo)產(chǎn)生，進而促進成功妊娠[46]。然而，Jablonowska等發(fā)現(xiàn)，妊娠前阻斷抗體陽性與RPL患者的妊娠結(jié)局無關(guān)[47]。盡管目前臨床實踐中并不常規(guī)檢測阻斷抗體，但在大多數(shù)調(diào)查RPL免疫療法療效的研究中，仍將其作為常規(guī)檢測指標，用于評估治療效果[48-50]。
蛻膜化異常可能是許多女性URPL病例的關(guān)鍵因素。免疫細胞，如NK細胞、巨噬細胞和T細胞，在蛻膜化過程中發(fā)揮關(guān)鍵作用。研究表明，RPL患者蛻膜組織內(nèi)這些免疫細胞的組成和功能均出現(xiàn)失調(diào)[51]。此外，在RPL患者的子宮內(nèi)膜中發(fā)現(xiàn)炎性小體的表達明顯增加[52, 53]。目前，指南僅提及在RPL中應(yīng)用NK細胞檢測，但并不推薦[35]。
單細胞RNA測序分析顯示，RPL患者樣本中促進胚胎發(fā)育的dNK亞群（dNK1）比例降低，而具有細胞殺傷和免疫反應(yīng)性的dNK亞群（dNK2）則顯著升高[30]。此外，CXCR4+ CD56 bright dNK細胞顯示出較低的活化和細胞毒性表型。在RPL患者中，這些細胞的數(shù)量明顯減少，且促進Th2分化的能力較弱[54]。NK細胞的活化與Tim-3的表達有關(guān)。約60%的dNK細胞表達Tim-3，并增加IL-4分泌、減少TNF-α和穿孔素[55]。既往研究表明，RPL患者的Tim-3+ dNK細胞比例減少。Tim-3在妊娠期間通過影響細胞因子分泌和抑制細胞毒性，對NK細胞發(fā)揮調(diào)節(jié)作用[9]。此外，腸道通透性增加可能是導(dǎo)致RPL免疫異常的機制之一[56，57]。腸道微生物群可能會通過誘導(dǎo)免疫反應(yīng)影響NK細胞功能，進一步加劇子宮內(nèi)膜免疫環(huán)境的失衡。
目前已在外周血、孕前子宮內(nèi)膜或流產(chǎn)后蛻膜組織中檢測到NK細胞[58，59]。然而，不同樣本來源的NK細胞亞群頻率存在顯著差異。相對而言，在子宮內(nèi)膜或蛻膜組織樣本中檢測NK細胞的準確率較高，但由于缺乏標準化檢測程序和檢測標準，并不適合臨床應(yīng)用。
M-CSF和IL-10是人類蛻膜中M2巨噬細胞的強誘導(dǎo)因子。在RPL患者中，血清M-CSF濃度顯著低于健康個體[60]。RPL婦女蛻膜中M1巨噬細胞的招募量大于M2巨噬細胞，與正常妊娠相反[61]。此外，RPL患者表現(xiàn)出細胞因子失衡，有利于向M1巨噬細胞極化。例如，胰島素樣生長因子II mRNA結(jié)合蛋白3在RPL病例的胎盤絨毛樣本中低表達，這可以激活滋養(yǎng)層細胞中的NF-κB通路，抑制IL-10表達，最終促進M1巨噬細胞的極化[62]。
T細胞相關(guān)因素可能參與URPL的發(fā)病機制，如CD4+/CD8+比率異常、CD4+ T細胞平衡向Th1偏移、Treg數(shù)量減少、免疫抑制功能減弱以及Th17細胞和Treg細胞失衡[9]。
人類蛻膜表達Galectin-9，它通過抑制T細胞活性、抑制Th1型細胞因子釋放和促進CD4+CD25+Foxp3+ Treg細胞增殖來調(diào)節(jié)免疫反應(yīng)[63]。Galectin-9具有多種生物學(xué)功能，對皮膚病變中的Th1/Th2免疫偏差有顯著影響。在RPL中，胎盤中Galectin-9的表達明顯減少，從而促進了Th1細胞的分化[64]。
最近的研究發(fā)現(xiàn)，Th17和Treg細胞比例失衡在URPL中發(fā)揮重要作用。Th17細胞分泌的IL-17和IL23可與Th1亞群協(xié)同介導(dǎo)組織炎癥和免疫反應(yīng)[3]。Wang等人發(fā)現(xiàn)，在URPL患者中，Treg細胞對Th17細胞活性的抑制作用減弱，表明Treg/Th17平衡向Th17占優(yōu)的方向偏移[65]。研究表明，URPL婦女外周血中CD4+ CD25+細胞的比例顯著低于正常妊娠早期婦女。此外，有報道稱URPL患者存在Treg細胞功能缺陷[66]。循環(huán)CD4+ CD25+ Foxp3+ Treg細胞數(shù)量減少，甚至可以作為有流產(chǎn)史孕婦再次流產(chǎn)風險的指標。
淋巴細胞免疫療法（lymphocyte immunotherapy，LIT）由Mowbray等人提出[67]，是一種針對URPL的主動免疫療法。淋巴細胞免疫療法主要是指從男性伴侶或無血緣關(guān)系的捐獻者身上抽取靜脈血，分離淋巴細胞，然后按照特定的治療方案靜脈注射淋巴細胞。迄今為止，LIT是針對RPL研究最為廣泛的免疫干預(yù)方法。LIT可以誘導(dǎo)URPL患者產(chǎn)生保護性抗體，如抗父系細胞毒性抗體、MLR阻斷因子、抗獨特型抗體和孕酮誘導(dǎo)阻斷因子等[16]。此外，LIT還能顯著降低Th1和Th17細胞水平，提高Th2和Treg細胞水平，從而導(dǎo)致IL-10和TGFβ的表達增強，這對維持妊娠期免疫耐受至關(guān)重要[68]。
Liu等人發(fā)現(xiàn)，LIT可顯著提高URPL患者的活產(chǎn)率，其中年齡較小和阻斷抗體陽性是LIT成功的獨立因素[49]。他們還進行了一項包括18項隨機對照試驗的薈萃分析，結(jié)果顯示在妊娠前及妊娠期間給予LIT的療效優(yōu)于僅在妊娠前給予LIT。此外，單次治療的劑量較低（尤其是少于1億個淋巴細胞或100毫升外周血）時，往往能取得更優(yōu)結(jié)果[69]。然而，目前關(guān)于LIT的用藥劑量、途徑和時間尚未達成共識[50, 70-72]。在治療過程中，患者可能出現(xiàn)局部反應(yīng)（如注射部位發(fā)紅、壓痕）甚至血源性感染[73]。目前，ESHRE指南不建議對URPL患者常規(guī)進行LIT，但阻斷抗體檢測陰性的患者可考慮接受LIT治療[3]。
靜脈注射免疫球蛋白（intravenous immunoglobulin, IVIG）是一種多克隆免疫球蛋白G的血漿制品，臨床上用于治療體液免疫缺陷和自身免疫性疾病。IVIG可通過減少細胞毒性T細胞和NK細胞、維持Th1/Th2平衡以及促進免疫抑制細胞因子（包括IL-10和TGF-β）的合成來調(diào)節(jié)免疫反應(yīng)[16，74]。一項研究在妊娠32周前為RPL患者注射IVIG（400mg/kg，每4周一次），結(jié)果顯示，IVIG治療可減輕Treg細胞的衰竭表型，從而改善妊娠預(yù)后[75]。另一項針對URPL患者的臨床研究發(fā)現(xiàn)，IVIG治療組（87.5%）的活產(chǎn)率高于安慰劑組（41.6%）[74]。此外，繼發(fā)性RPL患者可能從IVIG治療中獲益更多[76，77]。然而，由于用藥時間和劑量的差異，研究結(jié)果存在爭議。費用高昂、潛在副作用和適應(yīng)癥不明確等也限制了IVIG在RPL患者中的應(yīng)用。
脂肪乳劑是一種腸外營養(yǎng)制劑，可抑制NK細胞功能和炎性細胞因子的釋放，體外研究已證實其具有免疫調(diào)節(jié)特性。臨床研究證明，它對URPL和反復(fù)著床失敗（RIF）患者有效，尤其是對NK細胞活性異常的患者[78]。一些研究提供了中等程度的證據(jù)，表明靜脈注射脂肪乳劑療法可改善URPL婦女的生殖結(jié)局，尤其是活產(chǎn)率[79-81]。與IVIG相比，脂肪乳劑可能是一種更安全、更具成本效益的治療方案[82]。然而，部分研究報告了大劑量靜脈注射后的嚴重不良反應(yīng)，如急性腎損傷；且現(xiàn)有研究質(zhì)量不高，存在顯著異質(zhì)性。因此，仍需進一步研究以確定脂肪乳劑在臨床中的療效和安全性。
富血小板血漿（platelet-rich plasma, PRP）是從外周血中提取的血液濃縮物，其中血小板濃度至少是基線水平的35倍。它還包括一些細胞因子，如TGF-β和IL-1β[83]。PRP在膝關(guān)節(jié)骨關(guān)節(jié)炎和勃起功能障礙等領(lǐng)域廣泛應(yīng)用，通過調(diào)節(jié)細胞增殖、趨化和細胞因子分泌發(fā)揮重要作用。Li等人發(fā)現(xiàn)，在不明原因RIF患者中，PRP組的活產(chǎn)率、臨床妊娠率和著床率顯著高于安慰劑組[84]。一項網(wǎng)絡(luò)薈萃分析也顯示，宮腔內(nèi)注射人絨毛膜促性腺激素、粒細胞集落刺激因子、外周血單核細胞和PRP均能顯著改善RIF患者的臨床妊娠和活產(chǎn)率，其中PRP的效果最佳[85]。然而，關(guān)于PRP在URPL患者中的應(yīng)用，相關(guān)研究較為有限。
環(huán)孢素A（Cyclosporine A, CsA）是一種免疫抑制劑，在妊娠期器官移植患者中被證實是安全的[86]。此外，對新生兒出生后的隨訪顯示，其生長發(fā)育、免疫功能及其他方面均無異常[87]。在妊娠早期使用低劑量CsA可促進胎盤界面滋養(yǎng)層細胞的增殖、遷移和侵襲，從而促進胚胎著床[88]。同時，CsA可降低RPL患者的Th1/Th2比率，并促進IL-10和其他Th2型細胞因子的分泌，維持母胎免疫耐受[89]。Ling等人的研究進一步表明，小劑量CSA可提高URPL患者的活產(chǎn)率，且未出現(xiàn)母體或新生兒相關(guān)并發(fā)癥[90]。
他克莫司也是一種常用的免疫抑制劑。在一項隨機對照試驗中，對于外周血中IL-33/ST2水平升高或Th1/Th2細胞比例升高的難治性RPL患者，他克莫司顯示出潛在治療價值[91]。在另一項針對RIF患者的試驗中，從胚胎移植前2天開始給予他克莫司1-3 mg/d，持續(xù)至妊娠試驗共16天，顯著改善了妊娠結(jié)局[92]。西羅莫司（又稱雷帕霉素）最初于20世紀70年代作為低毒性抗真菌藥物開發(fā)，后因具有免疫抑制作用被用于預(yù)防器官移植排異反應(yīng)[93]。在小鼠模型中，西羅莫司可逆轉(zhuǎn)Treg細胞數(shù)量下降，提示其對Treg水平下降的URPL患者具有潛在治療價值[94]。鑒于CsA對滋養(yǎng)層細胞具有劑量依賴性雙重作用，且對后代的長期影響尚不明確，適當?shù)膭┝亢蜆藴驶闹委煏r間對確保成功妊娠和減少不良反應(yīng)至關(guān)重要，這一點同樣適用于其他免疫抑制劑。目前，指南僅建議確診自身免疫性疾病的RPL患者使用免疫抑制劑[35, 36]。
TNF-α是全身炎癥的標志物，在RPL患者的外周血漿中高表達[95]。TNF-α抑制劑是一類新型生物制劑，主要治療類風濕性關(guān)節(jié)炎、炎癥性腸病和其他以慢性炎癥為特征的疾病。一項針對75名RPL/RIF患者的回顧性研究發(fā)現(xiàn)，阿達木單抗（一種TNF-α抑制劑）聯(lián)合IVIG治療能有效提高活產(chǎn)率，且效果優(yōu)于單獨使用抗凝療法（肝素和阿司匹林）[96]。
依那西普是另一種TNF-α抑制劑，常用作抗風濕藥。一項隨機對照試驗證實了依那西普對難治性URPL患者的有效性。在妊娠第4周至第10周，依那西普能顯著降低患者的血漿TNF-α水平和pNK細胞活性[97, 98]。對于現(xiàn)有治療方案無效的難治性URPL患者，依那西普可能是一種選擇。然而，由于缺乏高質(zhì)量研究支持，其在妊娠期的安全性尚未確定。
合成皮質(zhì)類固醇（如潑尼松）對Th1/Th2細胞因子和NK細胞有免疫抑制作用，被認為是潛在的治療方法[9]。研究表明，潑尼松使用與RPL患者uNK細胞水平下降有關(guān)[99]。因此，相比于uNK細胞計數(shù)正常的患者，uNK細胞計數(shù)異常的URPL患者在接受糖皮質(zhì)激素治療后，生育結(jié)局有所改善[99，100]。然而，長期或大劑量使用皮質(zhì)類固醇會增加患者罹患高血壓和糖尿病的風險。目前，糖皮質(zhì)激素治療的最佳時機、劑量和療程仍在探索中，亟需開展大樣本隨機對照研究以制定循證指南。此外，進一步研究URPL患者的免疫生物標志物，對于指導(dǎo)糖皮質(zhì)激素治療至關(guān)重要[99, 101, 102]。
維生素D屬于類固醇激素，具有抗炎特性，通過抑制T細胞增殖和細胞因子合成，可下調(diào)IL-2、IFN-γ和TNF-α等炎癥基因轉(zhuǎn)錄[16]。維生素D不足與流產(chǎn)風險增加有關(guān)，補充維生素D可能有助于預(yù)防RPL[103-105]。在RPL患者中，維生素D不足患者的外周血中CD56+細胞毒性NK細胞活性及Th17/Treg比率顯著高于維生素D充足者[106，107]。一項臨床研究發(fā)現(xiàn)，URPL患者補充維生素D可降低外周血中Th、B和NK細胞以及IL2、TNF-α和IFN-γ的水平，同時增加IL-4和IL-10[108]。這些變化可能有助于促進成功妊娠。此外，無論是否患有RPL，維生素D補充劑已成為孕婦的常用處方。
孕酮對維持正常妊娠至關(guān)重要，作用機制包括促進免疫耐受、增加子宮血流量和增強子宮內(nèi)膜容受性。體外實驗發(fā)現(xiàn)，孕酮可下調(diào)Th1細胞釋放的細胞因子，同時促進Th2細胞分泌細胞因子[109]。此外，孕酮還能激活淋巴細胞合成孕酮誘導(dǎo)的阻斷因子，該因子能介導(dǎo)母胎界面的免疫耐受，抑制NK細胞的活性，從而對胎兒產(chǎn)生保護作用[110]。此外，多項研究表明，孕酮可誘導(dǎo)HLA-G的表達[111]。
多項臨床研究調(diào)查了孕酮在URPL患者中的作用，結(jié)果存在爭議[112-116]。一項薈萃分析表明，補充孕酮治療可能會降低URPL患者后續(xù)妊娠的流產(chǎn)率[117]。然而，一項針對836名婦女進行的多中心隨機試驗發(fā)現(xiàn)，在妊娠試驗呈陽性后，使用陰道微粒化孕酮的URPL婦女與使用安慰劑的婦女在活產(chǎn)率方面無顯著差異[113]。目前，國際婦產(chǎn)科聯(lián)盟不建議URPL患者在妊娠試驗呈陽性時開始使用陰道天然孕酮。相反，ESHRE指南建議，從黃體期開始服用孕酮，而不是等到妊娠試驗呈陽性后再服用，可能獲益更多[35]?？诜铣?/span>孕酮可能有一定效果，但需要大量安慰劑對照試驗來確定其最佳使用時機和劑量[118]。
蛻膜細胞釋放的G-CSF支持中性粒細胞的增殖和分化。有證據(jù)表明，G-CSF具有免疫調(diào)節(jié)特性，能夠誘導(dǎo)外周Treg細胞和髓源性抑制細胞的功能。它還能增強蛻膜巨噬細胞對血管內(nèi)皮生長因子的表達，促進血管重塑[119]。此外，體內(nèi)實驗證明，給予G-CSF可改善子宮內(nèi)膜厚度和卵母細胞質(zhì)量，可能促進胚胎著床[120]。在一項涉及68名URPL婦女的單中心研究中，G-CSF治療組的活產(chǎn)率（82.8%）明顯高于安慰劑組（48.5%）[121]。此外，與IVIG或抗凝治療相比，G-CSF可能是一種更有效的治療方案[122]。然而，Eapen等人發(fā)現(xiàn)，rhG-CSF組的不良反應(yīng)發(fā)生率（68.4% vs. 58.1%）和新生兒先天畸形率（2.1% vs. 2.0%）更高[123]。盡管G-CSF有治療RPL的潛力，但在推薦其用于臨床實踐之前，仍需在不同人群中進行更多高質(zhì)量的試驗以確認其療效。
母胎界面的免疫失衡是導(dǎo)致URPL的重要潛在機制。胎兒滋養(yǎng)層細胞、母體蛻膜基質(zhì)細胞和免疫細胞共同組成了一個復(fù)雜、有序、動態(tài)變化的分子調(diào)控網(wǎng)絡(luò)。事實上，這些成分的功能障礙或干擾都有可能導(dǎo)致RPL的發(fā)生。為了改善URPL患者的妊娠結(jié)局，多種免疫療法被提出并應(yīng)用，如LIT、IVIG、脂肪乳劑等。然而，由于研究人群和方法的異質(zhì)性，研究結(jié)果尚未定論。未來需要開展大樣本、多中心研究，為URPL患者的免疫療法提供高質(zhì)量的證據(jù)。
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