Exploring the correlation between immune function and poor prognosis in alloimmune recurrent miscarriage

doi:10.11958/20230467

Abstract

Abstract:

Objective To investigate the correlation between immune function and adverse pregnancy outcomes in pregnant women with recurrent alloimmune abortion (RSA). Methods A total of 136 patients with isoimmune RSA were included and divided into the pregnancy success group (50 cases) and pregnancy loss group (86 cases) according to pregnancy outcome. The age of patients and the number of abortions were collected, and glucocorticoid (GC), hydroxychloroquine sulfate (HCQ), aspirin (ASP), low molecular weight heparin, alfacalcalcitol, cyclosporine (CsA) and tacrolimus (FK506) were also collected. Levels of interleukin (IL-2), IL-4, IL-5, IL-6, IL-8, IL-10, IL-17 and tumor necrosis factor (TNF)-α were determined by enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate Logistic regression analysis was used to explore risk factors of pregnancy loss. Results Compared with the pregnancy loss group, levels of IL-6 and IL-10, the proportion of GC and low molecular weight heparin were increased in the pregnancy success group, while levels of IL-2 and IL-17 were decreased (P<0.05). There were no significant differences in age, abortion frequency, TNF-α level, HCQ, ASP, alfacalcalcitol, CsA and FK506 between the two groups. Single factor Logistic regression analysis showed that the use of IL-2, IL-6, IL-10, IL-17, GC and low molecular weight heparin were factors affecting pregnancy loss (P<0.01). Multivariate Logistic regression analysis showed that increased IL-17 was a risk factor for pregnancy loss, and increased IL-10, and the use of GC and low molecular weight heparin were protective factors (P<0.01). Conclusion Elevated IL-17 increases the risk of pregnancy loss in patients with isoimmune RSA, while elevated IL-10 and rational use of GC and low molecular weight heparin reduce the risk of pregnancy loss.

Key words: abortion, habitual, immunity, interleukin-17, interleukin-10, glucocorticoid, low molecular heparin

CLC Number:

R714.21

Figures/Tables 3

References 32

[1]	自然流产诊治中国专家共识编写组. 自然流产诊治中国专家共识(2020年版)[J]. 中国实用妇科与产科杂志, 2020, 36(11):1082-1090.
	Writing group of Chinese expert consensus on diagnosis and treatment of spontaneous abortion. Chinese expert consensus on diagnosis and treatment of spontaneous abortion(2020 edition)[J]. Chinese Journal of Practical Gynecology and Obstetrics, 2020, 36(11):1082-1090. doi:10.19538/j.fk2020110113.
[2]	DENG T, LIAO X, ZHU S. Recent advances in treatment of recurrent spontaneous abortion[J]. Obstet Gynecol Surv, 2022, 77(6):355-366. doi:10.1097/OGX.0000000000001033.
[3]	中国人体健康科技促进会生殖免疫专业委员会复发性流产病因检查专家共识编写组. 复发性流产病因检查专家共识[J]. 中国计划生育和妇产科, 2022, 14(2):3-9.
	Expert Consensus compilation group of Reproductive Immunization Committee of China Human Health Science and Technology Promotion Association for Recurrent Abortion etiology Examination. Expert consensus on etiological examination of recurrent miscarriage[J]. Chinese Journal Of Family Planning & Gynecotokology, 2022, 14(2):3-9. doi:10.3969/j.issn.1674-4020.2022.02.01.
[4]	赵颖, 章勤. 免疫机制诱导复发性流产的中西医研究概况[J]. 湖南中医杂志, 2020, 36(7):175-178.
	ZHAO Y, ZHANG Q. Research on immune mechanism induced recurrent abortion in Chinese and Western medicine[J]. Hunan Journal of Traditional Chinese Medicine, 2020, 36(7):175-178. doi:10.16808/j.cnki.issn1003-7705.2020.07.066.
[5]	WONG L F, PORTER T F, SCOTT J R. Immunotherapy for recurrent miscarriage[J]. Cochrane Database Syst Rev, 2014, 2014(10): CD000112. doi:10.1002/14651858.CD000112.pub3.
[6]	YANG X, TIAN Y, ZHENG L, et al. The update immune-regulatory role of pro- and anti-inflammatory cytokines in recurrent pregnancy losses[J]. Int J Mol Sci, 2022, 24(1):132. doi:10.3390/ijms24010132.
[7]	KOLANSKA K, DABI Y, DECHARTRES A, et al. Unexplained recurrent miscarriages:predictive value of immune biomarkers and immunomodulatory therapies for live birth[J]. Am J Reprod Immunol, 2021, 86(2):e13425. doi:10.1111/aji.13425.
[8]	CARP H. Immunotherapy for recurrent pregnancy loss[J]. Best Pract Res Clin Obstet Gynaecol, 2019, 60:77-86. doi:10.1016/j.bpobgyn.2019.07.005.
[9]	BEBDER A R, CHRISTIANSEN O B, ELSON J, et al. ESHRE guideline:recurrent pregnancy loss[J]. Hum Reprod Open, 2018, 2018(2): hoy004. doi:10.1093/hropen/hoy004.
[10]	赵静, 巩晓芸, 胡泊, 等. 复发性流产患者Th1/Th2细胞因子失衡及淋巴细胞主动免疫治疗的疗效[J]. 中国妇幼保健, 2013, 28(5):804-806.
	ZHAO J, GONG X Y, HU P, et al. Imbalance of Th1/Th2 cytokines in patients with recurrent abortion and curative effect of active immunotherapy of lymphocytes[J]. Maternal and Child Health Care of China, 2013, 28(5):804-806.
[11]	郑晶, 崔慧, 孙丽, 等. 同种免疫型复发性流产的病因学研究及治疗进展[J]. 中国生育健康杂志, 2020, 31(6):590-593.
	ZHENG J, CUI H, SUN L, et al. Research on the etiology and treatment progress of alloimmune recurrent miscarriage[J]. Chinese Journal of Reproductive Health, 2020, 31(6):590-593. doi:10.3969/j.issn.1671-878X.2020.06.025.
[12]	韦丽霞, 欧威铭, 吴涤. 复发性流产危险因素的研究现状[J]. 包头医学院学报, 2023, 39(3):89-96.
	WEI L X, OU W M, WU D. Current status of research on risk factors for recurrent miscarriage[J]. Journal of Baotou Medical College, 2023, 39(3):89-96. doi:10.16833/j.cnki.jbmc.2023.03.020.
[13]	赵英, 付冰冰, 张红英. 复发性流产患者外周血Th1/Th2平衡与蜕膜组织中细胞凋亡、侵袭的相关性[J]. 海南医学院学报, 2018, 24(24):2140-2144.
	ZHAO Y, FU B B, ZHANG H Y. Correlation of Th1/Th2 balance in peripheral blood with cell apoptosis and invasion in decid-ual tissue in patients with recurrent spontaneous abortion[J]. Journal of Hainan Medical University, 2018, 24(24):2140-2144. doi:10.13210/j.cnki.jhmu.20181109.001.
[14]	WANG W, SUNG N, GILMAN-SACHS A, et al. T helper(Th)cell profiles in pregnancy and recurrent pregnancy losses:Th1/Th2/Th9/Th17/Th22/Tfh Cells[J]. Front Immunol, 2020, 11:2025. doi:10.3389/fimmu.2020.02025.
[15]	徐澄, 陆启滨. Th1/Th2细胞因子失衡致复发性流产的机制及治疗[J]. 长春中医药大学学报, 2014, 30(5):934-936.
	XU C, LU Q B. Mechanism and treatment of the recurrent spontaneous abortion caused by Th1/Th2 cytokine imbalance[J]. Journal of Changchun University of Chinese Medicine, 2014, 30(5):934-936. doi:10.13463/j.cnki.cczyy.2014.05.067.
[16]	黄俊生, 刘晓洁. Th1/Th2型细胞因子、M-CSF、BA在原因不明复发性流产中的价值研究[J]. 河南医学研究, 2018, 27(22):4059-4062.
	HUANG J S, LIU X J. Study on the value of Th1/Th2 type cytokines, M-CSF and BA in recurrent miscarriage of unknown cause[J]. Henan Medical Research, 2018, 27(22):4059-4062. doi:10.3969/j.issn.1004-437X.2018.22.010.
[17]	MITCHELL R E, HASSAN M, BURTON B R, et al. IL-4 enhances IL-10 production in Th1 cells:implications for Th1 and Th2 regulation[J]. Sci Rep, 2017, 7(1):11315. doi:10.1038/s41598-017-11803-y.
[18]	TUR-TORRES M H, GARRIDO-GIMENEZ C, ALIJOTAS-REIG J. Genetics of recurrent miscarriage and fetal loss[J]. Best Pract Res Clin Obstet Gynaecol, 2017, 42:11-25. doi:10.1016/j.bpobgyn.2017.03.007.
[19]	程瑶瑶, 张雨婷, 母岺, 等. 原因不明复发性流产患者外周血PD-1和Th1/Th2型细胞因子表达及意义[J]. 热带医学杂志, 2022, 22(10):1361-1366.
	CHENG Y Y, ZHANG Y T, MU C, et al. The expression and significance of PD-1 and Th1/Th2 cytokines in peripheral blood of patients with unexplained recurrent miscarriage[J]. Journal of Tropical Medicine, 2022, 22(10):1361-1366. doi:10.3969/j.issn.1672-3619.2022.10.008.
[20]	NAKASHIMA A, ITO M, YONEDA S, et al. Circulating and decidual Th17 cell levels in healthy pregnancy[J]. Am J Reprod Immunol, 2010, 63(2):104-109. doi:10.1111/j.1600-0897.2009.00771.x.
[21]	SANTNER-NANAN B, PEEK M J, KHANAM R, et al. Systemic increase in the ratio between Foxp3⁺ and IL-17-producing CD4⁺ T cells in healthy pregnancy but not in preeclampsia[J]. J Immunol, 2009, 183(11):7023-7030. doi:10.4049/jimmunol.0901154.
[22]	PONGCHAROEN S, SUPALAP K. Interleukin-17 increased progesterone secretion by JEG-3 human choriocarcinoma cells[J]. Am J Reprod Immunol, 2009, 61(4):261-264. doi:10.1111/j.1600-0897.2009.00693.x.
[23]	SERESHKI N, GHARAGOZLOO M, OSTADI V, et al. Variations in T-helper 17 and regulatory T cells during the menstrual cycle in peripheral blood of women with recurrent spontaneous abortion[J]. Int J Fertil Steril, 2014, 8(1):59-66.
[24]	LIU Y S, WU L, TONG X H, et al. Study on the relationship between Th17 cells and unexplained recurrent spontaneous abortion[J]. Am J Reprod Immunol, 2011, 65(5):503-511. doi:10.1111/j.1600-0897.2010.00921.x.
[25]	LIANG P, MO M, LI G G, et al. Comprehensive analysis of peripheral blood lymphocytes in 76 women with recurrent miscarriage before and after lymphocyte immunotherapy[J]. Am J Reprod Immunol, 2012, 68(2):164-174. doi:10.1111/j.1600-0897.2012.01141.x.
[26]	LASH G E, BULMER J N, INNES B A, et al. Prednisolone treatment reduces endometrial spiral artery development in women with recurrent miscarriage[J]. Angiogenesis, 2011, 14(4):523-532. doi:10.1007/s10456-011-9237-x.
[27]	DAN S, WEI W, YICHAO S, et al. Effect of prednisolone administration on patients with unexplained recurrent miscarriage and in routine intracytoplasmic sperm injection:A meta-analysis[J]. Am J Reprod Immunol, 2015, 74(1):89-97. doi:10.1111/aji.12373.
[28]	MEKINIAN A, COHEN J, ALIJOTAS-REIG J, et al. Unexplained recurrent miscarriage and recurrent implantation failure:is there a place for immunomodulation?[J]. Am J Reprod Immunol, 2016, 76(1):8-28. doi:10.1111/aji.12493.
[29]	XU G L, HU X F, HAN Y M, et al. Clinical efficacy of low molecular heparin on unexplained recurrent spontaneous abortion[J]. Clin Lab, 2018, 64(6):1037-1040. doi:10.7754/Clin.Lab.2018.180130.
[30]	DE MOREUIL C, ALAVI Z, PASQUIER E. Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage[J]. Br J Clin Pharmacol, 2020, 86(1):39-49. doi:10.1111/bcp.14131.
[31]	AZIZI R, AHMADI M, DANAII S, et al. Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1/Th2 ratio[J]. J Cell Physiol, 2019, 234(10):19039-19047. doi:10.1002/jcp.28543.
[32]	LIU J, LI M, FU J, et al. Tacrolimus improved the pregnancy outcomes of patients with refractory recurrent spontaneous abortion and immune bias disorders:a randomized controlled trial[J]. Eur J Clin Pharmacol, 2023, 79(5):627-634. doi:10.1007/s00228-023-03473-9.

组别	n	年龄/岁	IL-2/（ng/L）			IL-6/（ng/L）		IL-10/（ng/L）			IL-17/（ng/L）		TNF-α/（ng/L）
妊娠丢失组	86	31.70±4.62	1.59（0.77，3.45）			1.16（0.89，2.08）		0.91（0.69，1.23）			1.84（1.23，3.77）		4.71（1.72，7.34）
妊娠成功组	50	31.76±4.58	1.12（0.77，1.12）			3.23（1.11，3.91）		1.49（0.88，3.67）			1.42（1.07，1.83）		1.95（1.09，5.00）
χ²、t或Z		0.076	2.548^＊			3.125^＊＊		4.146^＊＊			3.305^＊＊		1.972
组别	流产次数（≥3次/<3次）			GC	HCQ		ASP		低分子肝素	阿法骨化醇		CsA		FK506
妊娠丢失组	24/65			16（18.60）	62（72.09）		52（60.46）		14（16.28）	66（76.74）		13（15.12）		12（13.95）
妊娠成功组	15/35			29（58.00）	35（70.00）		38（76.00）		34（68.00）	36（72.00）		11（22.00）		5（10.00）
χ²	0.068			22.164^＊＊	0.068		3.409		37.035^＊＊	0.380		1.031		0.452

组别	n	年龄/岁	IL-2/（ng/L）			IL-6/（ng/L）		IL-10/（ng/L）			IL-17/（ng/L）		TNF-α/（ng/L）
妊娠丢失组	86	31.70±4.62	1.59（0.77，3.45）			1.16（0.89，2.08）		0.91（0.69，1.23）			1.84（1.23，3.77）		4.71（1.72，7.34）
妊娠成功组	50	31.76±4.58	1.12（0.77，1.12）			3.23（1.11，3.91）		1.49（0.88，3.67）			1.42（1.07，1.83）		1.95（1.09，5.00）
χ²、t或Z		0.076	2.548^＊			3.125^＊＊		4.146^＊＊			3.305^＊＊		1.972
组别	流产次数（≥3次/<3次）			GC	HCQ		ASP		低分子肝素	阿法骨化醇		CsA		FK506
妊娠丢失组	24/65			16（18.60）	62（72.09）		52（60.46）		14（16.28）	66（76.74）		13（15.12）		12（13.95）
妊娠成功组	15/35			29（58.00）	35（70.00）		38（76.00）		34（68.00）	36（72.00）		11（22.00）		5（10.00）
χ²	0.068			22.164^＊＊	0.068		3.409		37.035^＊＊	0.380		1.031		0.452

变量	β	SE	Wald χ²	P	OR（95%CI）
IL-2	0.502	0.165	9.233	0.002	1.652（1.195~2.284）
IL-6	-0.348	0.107	10.600	<0.001	0.706（0.572~0.871）
IL-10	-0.882	0.202	19.081	<0.001	0.414（0.279~0.615）
IL-17	0.517	0.172	8.993	0.003	1.667（1.196~2.350）
GC	-1.799	0.399	20.362	<0.001	0.116（0.076~0.362）
低分子肝素	-2.391	0.421	32.267	<0.001	0.092（0.040~0.209）

变量	β	SE	Wald χ²	P	OR（95%CI）
IL-2	0.502	0.165	9.233	0.002	1.652（1.195~2.284）
IL-6	-0.348	0.107	10.600	<0.001	0.706（0.572~0.871）
IL-10	-0.882	0.202	19.081	<0.001	0.414（0.279~0.615）
IL-17	0.517	0.172	8.993	0.003	1.667（1.196~2.350）
GC	-1.799	0.399	20.362	<0.001	0.116（0.076~0.362）
低分子肝素	-2.391	0.421	32.267	<0.001	0.092（0.040~0.209）

变量	β	SE	Wald χ²	P	OR（95%CI）
IL-2	-0.283	0.439	0.416	0.519	0.754（0.319~1.781）
IL-6	-0.210	0.144	2.121	0.145	0.811（0.611~1.075）
IL-10	-1.617	0.444	13.286	<0.001	0.198（0.083~0.473）
IL-17	1.285	0.408	9.950	0.002	3.614（1.627~8.029）
GC	-2.191	0.624	12.315	<0.001	0.112（0.033~0.380）
低分子肝素	-2.507	0.622	16.223	<0.001	0.082（0.024~0.276）
常数项	3.157	0.720	19.206	<0.001	23.498