血清肿瘤坏死因子与妊娠相关疾病的研究
Study on Serum Tumor Necrosis Factor and Pregnancy-Related Diseases
DOI: 10.12677/ACM.2024.141118, PDF, HTML, XML, 下载: 184  浏览: 340 
作者: 乌日汉, 孟海霞*:内蒙古医科大学附属医院,内蒙古 呼和浩特
关键词: 血清肿瘤坏死因子(TNF-α)不良妊娠结局Serum Tumor Necrosis Factor (TNF-α) Adverse Pregnancy Outcomes
摘要: 妊娠过程受环境、代谢及遗传等异常因素影响时,机体会发生一系列生理病理改变,进而导致子痫前期、妊娠期糖尿病、胎儿宫内生长受限等妊娠相关疾病,给胎儿和孕妇健康带来严重威胁。近年来,随着疾病机制研究的不断深入,研究人员发现TNF-α与妊娠相关疾病之间也存在关联。
Abstract: When the pregnancy process is affected by abnormal factors such as environment, metabolism and genetics, a series of physiological and pathological changes will occur in the body, which will lead to pregnancy-related diseases such as preeclampsia, gestational diabetes, and fetal growth restriction, posing a serious threat to the health of the fetus and pregnant women. In recent years, with the deepening of the study of the disease mechanism, researchers have found that there is also an asso-ciation between TNF-α and pregnancy-related diseases.
文章引用:乌日汉, 孟海霞. 血清肿瘤坏死因子与妊娠相关疾病的研究[J]. 临床医学进展, 2024, 14(1): 839-845. https://doi.org/10.12677/ACM.2024.141118

1. 引言

尽管世界人口已增加到30多亿,但妊娠仍然是一个成功率较低、灵活性低的过程。着床失败、自然流产(SM)、妊娠期高血压、妊娠期糖尿病、死产(SB)等的高发生率表明不良妊娠结局普遍存在,导致30%~60%的新生儿存活失败 [1] [2] 。不良妊娠结局的发病机制至今尚不清楚,预防这些结局的有效治疗策略仍然难以捉摸。为了更好地预测和改善妊娠结局,确定新的敏感、可靠的生物标志物并开发新的靶向治疗至关重要。怀孕和分娩期间的生理过程是紧密而特殊的。特别是,宫腔创造了一个局部环境来保护胚胎免受排斥并调节胎儿的生长和发育。分娩是一个独特的生理过程,其中炎症性免疫环境将免疫反应从免疫耐受状态转变为激活状态,导致肌层激活 [3] [4] [5] 。因此,胎儿和母体免疫耐受之间的良好平衡在维持正常妊娠中起着重要作用。在最近的观察性研究中,不良妊娠结果可能是由母体免疫耐受失衡或过早或过度炎症的直接刺激引起的 [6] 。异常细胞因子,如肿瘤坏死因子(TNF-α)与围产期不良结局的风险有关,例如SM、PTB和胎儿宫内生长受限 [7] 。

肿瘤坏死因子(TNF-α)是由激活的巨噬细胞、肥大细胞和内皮细胞产生的一种促炎的Th1细胞因子 [8] ,也是最重要的炎性细胞因子之一。在生理条件下,肿瘤坏死因子参与免疫监视和防御,细胞稳态,防止某些神经损伤以及控制细胞存活、增殖、迁移和分化 [9] 。而在女性妊娠期间,TNF-α具有双重作用,生理浓度的TNF-α有利于早期胚胎发育和黄体维持。而高于生理浓度的TNF-α对精子活力、精子芽透卵细胞、精卵结合及早期胚胎发育具有不良作用,甚至可导致妊娠不良结局。因此,在导致不良妊娠结局相关的研究领域中,肿瘤坏死因子逐渐成为热点。

2. TNF-α与妊娠相关疾病

妊娠过程受环境、代谢及遗传等异常因素影响时,机体会发生一系列生理病理改变,进而导致子痫前期、妊娠期糖尿病、胎儿宫内生长受限等妊娠相关疾病,给胎儿和孕妇健康带来严重威胁。近年来,随着疾病机制研究的不断深入,研究人员发现TNF-α与妊娠相关疾病之间也存在关联。鉴于此,本文对TNF-α在不同妊娠相关疾病中的研究进展综述如下,以期为妊娠相关疾病的诊治提供新的方向。

2.1. TNF-α与子痫前期

子痫前期是妊娠期高血压疾病较为严重的一种,妊娠20周后以水肿、蛋白尿、高血压为主要临床表现,严重影响妊娠结局、身心健康、生活质量 [10] 。根据相关流行病学研究,子痫前期是一种影响全球3%~5%孕妇的疾病 [11] ,而中国的患病率约为10% [12] 。子痫前期的发病机制尚不完全清楚,认为内皮损伤、无菌性全身炎症和胎盘“浅表胎盘”在子痫前期(PE)的发病机制中起作用 [13] 。肿瘤坏死因子-α (TNF-α)作为一种促炎细胞因子,能够在亚细胞水平上刺激一系列级联反应,诱导包括TNF-α在内的各种促炎因子的表达,介导母体血管内皮的广泛损伤并引起PE的典型症状。此外,TNF-α作用于血管内皮细胞,从而增加毛细血管通透性,诱发血栓形成,导致局部组织缺血缺氧。研究表明 [14] 临床子痫前期患者血清中TNF-α水平高于正常孕妇,而胎盘组织中TNF-α表达也随着病情的进一步升高而升高,提示TNF-α在先兆子痫的病理发展中发挥作用。洪 [15] 等报道,先兆子痫患者的血清中含有大量由白细胞激活的炎症介质,并且子痫前期与生物体中炎症反应的存在之间存在实质性关联。在这项研究中,我们发现,相对于健康对照组,早发性和晚发性患者中外周血中的TNF-α水平升高,这表明子痫前期患者的免疫炎症机制已经受到干扰,并且早发患者的TNF-α水平高于晚期患者。这被认为是由于怀孕期间滋养层细胞的相对缺氧,这增加了促炎细胞因子TNF-α的表达。由于TNF-α作用于胎盘区域的血管内皮细胞和滋养层细胞,导致内皮细胞受损,毛细血管通透性增加,刺激血栓形成,导致局部组织缺血缺氧、浅表胎盘着床和子痫前期 [16] 。

2.2. TNF-α与GDM

妊娠期糖尿病(gestational diabetes mellitus, GDM)是在怀孕期间发病或首次发现的任何程度的糖耐量异常 [17] ,是妊娠期常见的代谢并发症之一,不仅在短期内而且在长期内,都会增加母亲及其后代的不良妊娠结局风险 [18] 。随着经济水平的提高,人们的饮食结构和生活习惯发生改变,全球GDM发生率随之升高。据统计,全球GDM发病率为13.2% [19] ,中国为14.8% [20] 。GDM是一种慢性炎性疾病,炎症因子可能通过抑制胰岛素信号转导引起胰岛素抵抗(insulin resistance, IR),参与GDM的发病 [21] 。有相关研究表明,GDM女性中母体炎性细胞因子(TNF-α)水平较正常妊娠孕妇高,但其参与GDM病理过程的机制尚不清楚。Teng等 [22] 研究发现,硫化氢(hydrogen sulfide, H2S)可抑制胰岛素释放和胰岛β细胞的活性,当血糖升高时H2S下降,同时伴随TNF-α的升高,这可能是GDM炎症机制的一环。值得注意的是,随着母体TNF-α水平的升高,孕早期胎盘分泌的粒细胞–巨噬细胞集落刺激因子、趋化因子配体5和白细胞介素(interleukin, IL)-10增多,而IL-6和IL-8水平无明显变化,表明在炎症初期体内可能存在抑制炎症状态的保护机制 [23] 。可见,TNF-α通过调节炎症因子影响GDM病理过程的因素众多,且机制复杂,有待进一步研究。促炎因子TNF-α已被证实对于GDM的发生具有较好的预测价值,但是GDM的病理过程涉及的炎症介质众多且彼此影响,炎症机制十分复杂,未来需要大量研究进一步探讨。

2.3. TNF-α与胎膜早破

胎膜早破(PPROM)是指胎膜在临产前发生自发性破裂,又称临产前胎膜自然破裂,可分为足月胎膜早破和未足月胎膜早破。PPROM使约3%的妊娠复杂化,并导致约三分之一的早产。胎膜早破的原因尚不清楚,但最近,新的理论认识到PPROM可能是由复杂和多方面的途径引起的,通过改变胶原蛋白网络和/或激活由细菌产物或促炎细胞因子(TNF-α)触发的基质金属蛋白酶,导致膜形态减弱 [24] 。有研究表明 [25] ,与正常足月分娩者相比,胎膜早破患者胎膜、血清以及羊水中的TNF-α表达更高,表明胎膜早破后孕妇体内发生炎性反应导致大量细胞因子释放,使胎膜早破孕妇细胞因子总体水平高。研究还表明,母血中TNF-α水平与破膜时间有明显关系,及破膜时间越长,机体越有充足的时间对细菌及其产物产生应答,TNF-α产生越多 [26] 。可能原因是,TNF-α参与了机体的炎症反应过程,触发胎膜组织中CasDase基因表达,诱导胎膜细胞凋亡,从而导致胎膜早破。

2.4. TNF-α与早产

根据世界卫生组织的定义,早产被定义为终止妊娠少于37整周 [27] ,是五岁以下儿童死亡的主要原因。一般来说,早产对早产儿的健康有负面影响,给早产儿家庭和社会造成负担。早产与遗传因素、炎症和免疫力有关 [28] 。一方面,胎膜早破(PROM)是早产的原因之一。在小鼠模型中,胎盘组织中TNF-α和IL-6上调导致PROM [29] 。王等证明TNF-α引起的胎儿膜细胞凋亡增加与PROM有关,进一步导致早产 [30] 。另一方面,子宫收缩力异常也会导致早产。许多研究表明,TNF-α与子宫肌层的收缩力有一定的相关性,主要是通过影响黄体酮(PG)和基质金属蛋白肽酶9 (MMP9)的表达。子宫肌层中PG和MMP9的表达和敏感性的增加将导致子宫收缩和分娩 [31] [32] 。具体而言,据报道TNF-α会降低滋养层细胞中NAD + 依赖性15-羟基前列腺素脱氢酶(PGDH)的活性和表达,导致母体PE和早产 [33] 。最近的进展表明,TNF家族可能调节导致早产的巨噬细胞功能障碍,但具体的分子机制需要进一步研究。

2.5. TNF-α与胎儿生长受限

胎儿生长受限(IUGR)被定义为胎儿预期生长潜力的损害,估计胎儿体重小于胎龄小10%。母体营养、胎盘运输和胎儿遗传潜力的异常可能导致胎儿的异常生长发育。Azizieh和Raghupathy等人发现IUGR患者外周血单核细胞中TNF-α的表达高于正常孕妇,说明了TNF-α在IUGR发生中的潜在作用 [34] 。然而,IUGR中TNF-α免疫学研究的具体机制是有限的。胎儿血管疾病是IUGR的致病机制。TNF-α直接损害内皮细胞,损害滋养层细胞的侵袭和融合 [35] [36] ,并损害螺旋动脉的重塑。此外,TNF-α还可以干扰血液凝固系统,导致胎盘血栓形成和加重胎盘灌注不足 [37] [38] 。因此,这些表明TNF-α与IUGR和骨骼迟缓密切相关。埃尔法约米等。证明IUGR血清中抗苗勒管激素(AMH)、IL-6和TNF-α高于正常妊娠,可作为IUGR的有用生化标志物。然而,关于IUGR调查的报告很少 [39] 。值得注意的是,需要更多的临床研究来确定它们是IUGR生物标志物的诊断,治疗和预防。在小鼠中,阻断TNF-α可以改善螺旋动脉重塑和妊娠结局 [40] 。因此,TNF-α为IUGR的治疗和预防提供了新的选择。目前,关于IUGR中TNF家族的研究屈指可数,TNF在IUGR发病机制中的作用需要进一步研究。

2.6. TNF-α与其他不良妊娠结局

据兰等报道,TNF-α和Th1/Th2比率水平升高与胚胎停滞率呈阳性 [41] 。李等首先发现TNF-α基因多态性与复发流产风险增加有关 [42] 。随后,其他研究小组进一步证明了TNF-α在蜕膜组织和复发性流产外周血中的高表达 [43] 。丰塞卡等发现TNF-α在流产的蜕膜组织中的高表达可以抑制胚胎干细胞的分化并损害蜕膜化,从而干扰囊胚植入和/或妊娠维持 [44] 。杨等人的最新研究。结果表明,dNK细胞在自发流产组织中高度表达TNF-α,TNF-α诱导dNK细胞中芳烃受体表达上调,从而增强蜕膜自然杀伤细胞(dNK细胞)的细胞毒性,使dNK细胞对胎儿产生免疫反应,导致流产。

3. 总结

总之,成功妊娠需要蜕膜免疫细胞和炎性细胞因子之间的胎儿–母体免疫串扰。TNF-α失调可能导致不良妊娠结局。在妊娠过程中,高TNF-α浓度不仅增加NK细胞的细胞毒性并刺激B细胞,而且破坏了Th1/Th2和Th17/Treg细胞的平衡,增加了滋养层的死亡,损害了其侵袭和融合,损害了内皮细胞,影响了蜕膜化。因此,上述机制诱发妊娠并发症,即PE,IUGR,SA和早产。尽管如此,TNF-α的特殊机制仍需进一步研究。

NOTES

*通讯作者。

参考文献

[1] Quenby, S., Gallos, I.D., Dhillon-Smith, R.K., Podesek, M., Stephenson, M.D., Fisher, J., et al. (2021) Miscarriage Matters: The Epidemiological, Physical, Psychological, and Economic Costs of Early Pregnancy Loss. The Lancet, 397, 1658-1667.
https://doi.org/10.1016/S0140-6736(21)00682-6
[2] Wang, H., Jiang, J., Jin, T., Wang, Y., Li, M., Huang, S., et al. (2023) Associations of Circulation Levels of Cytokines with Birthweight, Preterm Birth, Spontaneous Miscarriages, and Stillbirth: A Mendelian Randomization Analysis. Frontiers in Genetics, 14, Article ID: 1113804.
https://doi.org/10.3389/fgene.2023.1113804
[3] Green, E.S. and Arck, P.C. (2020) Pathogenesis of Preterm Birth: Bidirectional Inflammation in Mother and Fetus. Seminars in Immunopathology, 42, 413-429.
https://doi.org/10.1007/s00281-020-00807-y
[4] Menon, R. (2022) Fetal Inflammatory Response at the Feto-maternal Interface: A Requirement for Labor at Term and Preterm. Immunological Reviews, 308, 149-167.
https://doi.org/10.1111/imr.13075
[5] Meuleman, T., Lashley, L.E.L.O., Dekkers, O.M., van Lith, J.M.M., Claas, F.H.J. and Bloemenkamp, K.W.M. (2015) HLA Associations and HLA Sharing in Recurrent Miscarriage: A Systematic Review and Meta-Analysis. Human Immunology, 76, 362-373.
https://doi.org/10.1016/j.humimm.2015.02.004
[6] Robertson, S.A., Care, A.S. and Moldenhauer, L.M. (2018) Regulatory T Cells in Embryo Implantation and the Immune Response to Pregnancy. The Journal of Clinical Investiga-tion, 128, 4224-4235.
https://doi.org/10.1172/JCI122182
[7] Dai, F.F., Hu, M., Zhang, Y.W., Zhu, R.H., Chen, L.P., Li, Z.D., et al. (2022) TNF-α/Anti-TNF-α Drugs and Its Effect on Pregnancy Outcomes. Expert Reviews in Molecular Medicine, 24, e26.
https://doi.org/10.1017/erm.2022.18
[8] Alijotas-Reig, J., Esteve-Valverde, E., Ferrer-Oliveras, R., et al. (2017) Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review. Clinical Reviews in Allergy & Immunology, 53, 40-53.
https://doi.org/10.1007/s12016-016-8596-x
[9] Sriram, K. and O’Callaghan, J.P. (2007) Divergent Roles for Tu-mor Necrosis Factor-Alpha in the Brain. Journal of Neuroimmune Pharmacology, 2, 140-153.
https://doi.org/10.1007/s11481-007-9070-6
[10] Liong, S., Barker, G. and Lappas, M. (2018) Bromodomain Pro-tein BRD4 Is Increased in Human Placentas from Women with Early-Onset Preeclampsia. Reproduction, 155, 573-582.
https://doi.org/10.1530/REP-17-0744
[11] Yang, H., He, W., Eriksson, M., et al. (2018) Inherited Factors Contrib-ute to an Inverse Association between Preeclampsia and Breast Cancer. Breast Cancer Research, 20, 6-14.
https://doi.org/10.1186/s13058-017-0930-6
[12] Wu, L., Chen, Y., Guan, X., et al. (2021) Relationship between Pre-Pregnancy BMI and the Occurrence and Clinical Characteristics of Pre-Eclampsia. Chinese Journal of Obstetrics and Gynecology, 56, 96-101.
[13] LaMarca, B., Cornelius, D.C. and Lamarca, B. (2016) The Role of Inflammation in the Pathology of Preeclampsia. Clinical Science, 130, 409-419.
https://doi.org/10.1042/CS20150702
[14] Mohammadpour-Gharehbagh, A., et al. (2019) The Role of TNF-α and TLR4 Polymorphisms in the Placenta of Pregnant Women Complicated by Preeclampsia and in Silico Analysis. Interna-tional Journal of Biological Macromolecules, 134, 1205-1215.
https://doi.org/10.1016/j.ijbiomac.2019.05.040
[15] Hung, T.-H., Charnock-Jones, D.S., Skepper, J.N., et al. (2004) Secretion of Tumor Necrosis Factor-Alpha from Human Placental Tissues Induced by Hypoxia-Reoxygenation Causes Endothelial Cell Activation in Vitro: A Potential Mediator of the Inflammatory Response in Preeclampsia. The American Journal of Pathology, 164, 1049-1061.
https://doi.org/10.1016/S0002-9440(10)63192-6
[16] Zhou, Y. and Gan, G. (2023) The Levels of Peripheral Blood TNF-α, Decorin and Neutrophils MAPK1 mRNA Levels of Patients with Preeclampsia and Their Clinical Significance. The Journal of Maternal-Fetal & Neonatal Medicine, 36, Article ID: 2183745.
https://doi.org/10.1080/14767058.2023.2183745
[17] 杨蕊华, 袁仙仙, 李光辉. 炎症相关指标与妊娠期糖尿病关系的研究进展[J]. 中华围产医学杂志, 2023, 26(4): 344-349.
https://doi.org/10.3760/cma.j.cn113903-20221004-00865
[18] Juan, J. and Yang, H. (2020) Prevalence, Preven-tion, and Lifestyle Intervention of Gestational Diabetes Mellitus in China. International Journal of Environmental Re-search and Public Health, 17, Article No. 9517.
https://doi.org/10.3390/ijerph17249517
[19] American Diabetes Association Professional Practice Committee (2022) 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care, 45, S17-S38.
https://doi.org/10.2337/dc22-S002
[20] International Diabetes Federation (2021) IDF Diabetes Atlas Ninth Edition 2019.
https://diabetesatlas.org/upload/resources/material/20200302_133351_IDFATLAS9e-final-web.pdf
[21] Moham-med, A. and Aliyu, I.S. (2018) Maternal Serum Level of TNF-α in Nigerian Women with Gestational Diabetes Mellitus. The Pan African Medical Journal, 31, Article No. 250.
https://doi.org/10.11604/pamj.2018.31.250.16989
[22] Teng, Y., Xuan, S., Jiang, M., et al. (2020) Expression of H2S in Gestational Diabetes Mellitus and Correlation Analysis with Inflammatory Markers IL-6 and TNF-α. Journal of Diabetes Research, 2020, Article ID: 3085840.
https://doi.org/10.1155/2020/3085840
[23] Siwetz, M., Blaschitz, A., El-Heliebi, A., et al. (2016) TNF-α Alters the Inflammatory Secretion Profile of Human First Trimester Placenta. Laboratory Investigation, 96, 428-438.
https://doi.org/10.1038/labinvest.2015.159
[24] Ronzoni, S., Boucoiran, I., Yudin, M.H., Coolen, J., Pylypjuk, C., Melamed, N., et al. (2022) Guideline No. 430: Diagnosis and Management of Preterm Prelabour Rupture of Membranes. Journal of Obstetrics and Gynaecology Canada, 44, 1193-1208.e1.
https://doi.org/10.1016/j.jogc.2022.08.014
[25] 刘秋兰, 钱晶晶, 俞燕燕. 早产胎膜早破危险因素、胎盘病理变化及妊娠结局分析[J]. 中国妇幼保健, 2018, 33(9): 1981-1983.
[26] 王丽, 张为远, 王玉芝, 等. 胎膜早破孕妇血清和羊水白细胞介素6及肿瘤坏死因子水平的研究[J]. 中华妇产科杂志, 1998, 33(6): 328-330.
[27] Organization WH (1977) WHO: Recommended Definitions, Termi-nology and Format for Statistical Tables Related to the Perinatal Period and Use of a New Certificate for Cause of Peri-natal Deaths. Modifications Recommended by FIGO as Amended October 14, 1976. Acta Obstetricia et Gynecologica Scandinavica, 56, 247-253.
https://doi.org/10.3109/00016347709162009
[28] Gomez-Lopez, N., et al. (2020) Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes. Cell Reports, 32, Article ID: 107874.
https://doi.org/10.1016/j.celrep.2020.107874
[29] Li, W., et al. (2020) Upregulation of TNF-alpha and IL-6 Induc-es Preterm Premature Rupture of Membranes by Activation of ADAMTS-9 in Embryonic Membrane Cells. Life Sciences, 260, Article ID: 118237.
https://doi.org/10.1016/j.lfs.2020.118237
[30] Wang, X.J., Li, L. and Cui, S.H. (2009) Role of Collagen III, CTGF and TNF-α in Premature Rupture of Human Fetal Membranes. Journal of Sichuan University. Medical Science Edition, 40, 658-661, 75.
[31] Ulrich, C.C., et al. (2019) Matrix Metalloproteinases 2 and 9 Are Elevated in Human Preterm La-boring Uterine Myometrium and Exacerbate Uterine Contractility Dagger. Biology of Reproduction, 100, 1597-1604.
https://doi.org/10.1093/biolre/ioz054
[32] Menon, R., et al. (2006) Analysis of Association between Maternal Tu-mor Necrosis Factor-Alpha Promoter Polymorphism (-308), Tumor Necrosis Factor Concentration, and Preterm Birth. American Journal of Obstetrics and Gynecology, 195, 1240-1248.
https://doi.org/10.1016/j.ajog.2006.05.037
[33] Pomini, F., Caruso, A. and Challis, J.R. (1999) Interleukin-10 Modifies the Effects of Interleukin-1beta and Tumor Necrosis Factor-α on the Activity and Expression of Prostaglandin H Synthase-2 and the NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase in Cultured Term Human Villous Trophoblast and Chorion Trophoblast Cells. Journal of Clinical Endocrinology and Metabolism, 84, 4645-4651.
[34] Azizieh, F.Y. and Raghupathy, R.G. (2015) Tumor Necrosis Factor-alpha and Pregnancy Complica-tions: A Prospective Study. Medical Principles and Practice: International Journal of the Kuwait University, Health Sci-ence Centre, 24, 165-170.
https://doi.org/10.1159/000369363
[35] Cotechini, T., et al. (2014) Inflammation in Rat Pregnancy Inhibits Spiral Artery Remodeling Leading to Fetal Growth Restriction and Features of Preeclampsia. Journal of Experimental Medicine, 211, 165-179.
https://doi.org/10.1084/jem.20130295
[36] Cotechini, T. and Graham, C.H. (2015) Aberrant Maternal Inflammation as a Cause of Pregnancy Complications: A Potential Therapeutic Target? Placenta, 36, 960-966.
https://doi.org/10.1016/j.placenta.2015.05.016
[37] Hunt, J.S., Atherton, R.A. and Pace, J.L. (1990) Differential Responses of Rat Trophoblast Cells and Embryonic Fibroblasts to Cytokines That Regulate Proliferation and Class I MHC Antigen Expression. Journal of Immunology, 145, 184-189.
https://doi.org/10.4049/jimmunol.145.1.184
[38] Bevilacqua, M.P., et al. (1986) Recombinant Tumor Necrosis Factor Induces Procoagulant Activity in Cultured Human Vascular Endothelium: Characterization and Comparison with the Actions of Interleukin 1. Proceedings of the National Academy of Sciences of the United States of America, 83, 4533-4537.
https://doi.org/10.1073/pnas.83.12.4533
[39] Elfayomy, A.K., et al. (2013) Serum Levels of Adreno-medullin and Inflammatory Cytokines in Women with Term Idiopathic Intrauterine Growth Restriction. Journal of Ob-stetrics and Gynaecology, 33, 135-139.
https://doi.org/10.3109/01443615.2012.721821
[40] Gelber, S.E., et al. (2015) Prevention of Defective Placenta-tion and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency. Journal of Immunology, 195, 1129-1138.
https://doi.org/10.4049/jimmunol.1402220
[41] Lan, Y., et al. (2021) Progesterone-Induced Blocking Fac-tor-Mediated Th1/Th2 Balance Correlates with Fetal Arrest in Women Who Underwent in Vitro Fertilization and Embryo Transfer. Clinical Immunology, 232, Article ID: 108858.
https://doi.org/10.1016/j.clim.2021.108858
[42] Li, H.H., et al. (2016) Association of TNF-α Genetic Polymor-phisms with Recurrent Pregnancy Loss Risk: A Systematic Review and Meta-Analysis. Reproductive Biology and En-docrinology: RB&E, 14, Article No. 6.
https://doi.org/10.1186/s12958-016-0140-6
[43] Li, S., et al. (2017) Expression Level of TNF-α in Decidual Tissue and Peripheral Blood of Patients with Recurrent Spontaneous Abortion. Central-European Journal of Immunology, 42, 156-160.
https://doi.org/10.5114/ceji.2017.69357
[44] Fonseca, B.M., et al. (2020) Decidual NK Cell-Derived Conditioned Medium from Miscarriages Affects Endometrial Stromal Cell Decidualisation: Endocannabinoid Anandamide and Tu-mour Necrosis Factor-Alpha Crosstalk. Human Reproduction, 35, 265-274.
https://doi.org/10.1093/humrep/dez260