复发性流产患者血清sST2、PLGF水平与再发自然流产的相关性研究

Study on association between serum sST2 and PLGF levels and recurrence of spontaneous abortion in patients with recurrent spontaneous abortion

摘要

目的 分析复发性流产(RSA)患者血清可溶性生长刺激表达因子2(sST2)、胎盘生长因子(PLGF)水平及其与再发自然流产的相关性,以期为复发性流产患者再次发生流产的风险评估提供支持。方法 于2021年3月至2022年12月收集在本院确诊并治疗的RSA患者作为RSA组(n=205),另选取同期无相关不良孕产史孕妇作为对照组(n=205).根据RSA患者孕14周内是否发生流产将患者分为流产组(n=85)和未流产组(n=120).采用酶联免疫吸附法检测血清sST2、PLGF水平.分别采用Pearson和Spearman相关分析sST2、PLGF水平与孕酮、流产次数的相关性.采用Logistic回归分析RSA患者发生自然流产的影响因素;使用受试者特征(ROC)曲线分析RSA患者血清sST2、PLGF水平与再次发生自然流产的相关性。结果 RSA组血清sST2水平显著高于对照组,PLGF水平显著低于对照组(t值分别为19.451、10.753,P<0.05);RSA患者中,流产组血清sST2显著高于未流产组,PLGF水平显著低于未流产组(t值分别为6.629、6.409,P<0.05).RSA患者血清sST2与PLGF水平呈负相关(r=-0.416,P<0.001);血清sST2水平与流产次数呈正相关、与孕酮呈负相关(r=0.404、-0.405,P<0.001);血清PLGF水平与流产次数呈负相关、与孕酮呈正相关(r=-0.417、0.456,P<0.001).Logistic回归分析结果显示,sST2、PLGF、流产次数、孕酮均为RSA患者再次发生自然流产的影响因素,OR值及其95%置信区间分别为1.433(1.237~1.660)、0.208(0.086~0.505)、1.256(1.137~1.388)、0.242(0.101~0.581),均P<0.05.sST2、PLGF联合检测评估RSA是否再次发生自然流产的AUC为0.824(95%CI:0.765~0.874),敏感度为84.71%,特异度为71.67%,二者联合优于sST2、PLGF各自单独评估(ZsST2-联合=3.113,P=0.002,ZPLGF-联合=2.995,P=0.003)。结论 RSA患者血清sST2水平升高、PLGF水平下降与再发自然流产关系密切,二者联合对评估RSA患者再发自然流产的风险评估具有一定价值.

Abstract

Objective To analyze associations of serum levels of soluble suppression of tumorigenicity-2 (sST2) and placental growth factor (PLGF) with recurrence of spontaneous abortion in early pregnant women with recurrent spontaneous abortion (RSA), so as to provide support for evaluating risk of recurrence of spontaneous abortion in RSA patients. Methods A total of 205 RSA patients who were diagnosed and treated in our hospital from March 2021 to December 2022 were selected as RSA group, and other 205 healthy early pregnant women without related adverse pregnancy and childbirth histories in the same period were selected as the controls. RSA patients were divided into RSA group (n=85) and non-RSA group (n=120) according to whether they experienced recurrent spontaneous abortion within 14 weeks of gestation. Enzyme-linked immunosorbent assay was applied to detect serum levels of sST2 and PLGF. Pearson and Spearman correlation analyses were applied to analyze correlations of serum levels of sST2 and PLGF with progesterone, frequency of abortion. Logistic regression was applied to analyze influencing factors of spontaneous abortion in RSA patients. Receiver operating characteristic (ROC) curve was applied to analyze predictive values of serum levels of sST2 and PLGF for recurrence of spontaneous abortion. Results The serum level of sST2 of RSA patients was significantly higher than that in the control group, while the serum level of PLGF was significantly lower than that in the control group (t=19.451 and 10.753 respectively, both P<0.05). Among the RSA patients, the serum level of sST2 of the patients with recurrent spontaneous abortion was significantly higher than that, while the serum level of PLGF was significantly lower than that of the patients without recurrence spontaneous abortion (t=6.629 and 6.409 respectively, both P<0.05). Correlation analysis showed that in the RSA patients, the serum level of sST2 was negatively correlated with the serum level of PLGF (r=-0.416, P<0.001), and the serum level of sST2 was positively correlated with frequency of spontaneous abortion and negatively correlated with the serum progesterone level (r=0.404 and -0.405 respectively, both P<0.001), while the serum level of PLGF was negatively correlated with frequency of spontaneous abortion and positively correlated with the serum level of progesterone (r=-0.417 and 0.456 respectively, both P<0.001). Logistic regression analysis showed that sST2, PLGF, frequency of spontaneous abortion and progesterone were all influencing factors for recurrence of spontaneous abortion in RSA patients [OR (95%CI)=1.433 (1.237-1.660), 0.208 (0.086-0.505), 1.256 (1.137-1.388) and 0.242 (0.101-0.581) respectively, all P<0.05]. The area under the curve (AUC) of the combined detection of sST2 and PLGF for predicting recurrence of spontaneous abortion was 0.824 (95%CI: 0.765-0.874), the sensitivity was 84.71% and the specificity was 71.67%, which was superior to those of single sST2 and single PLGF alone (ZsST2-combination=3.113, P=0.002; ZPLGF-combination=2.995, P=0.003). Conclusion Evaluated serum level of sST2 and lowered serum level of PLGF are closely related to recurrence of spontaneous abortion in RSA patients, and combined detection of serum sST2 and PLGF levels has some values for predicting risk of recurrence of spontaneous abortion in RSA patients.

关键词

复发性流产 / 可溶性生长刺激表达因子2 / 胎盘生长因子 / 自然流产

Key words

recurrent spontaneous abortion / soluble suppression of tumorigenicity-2 / placental growth factor / spontaneous abortion

参考文献

[1] La X, Wang W, Zhang M, et al. Definition and Multiple Factors of Recurrent Spontaneous Abortion[J]. Adv Exp Med Biol, 2021, 1300(1): 231-257.

[2] Sciatti E, Merlo A, Scangiuzzi C, et al. Prognostic Value of sST2 in Heart Failure[J]. J Clin Med, 2023, Jun, 12(12): 3970.

[3] 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.

[4] Salker MS, Nautiyal J, Steel JH, et al. Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss[J]. PLoS One, 2012, 7(12): e52252.

[5] Albonici L, Benvenuto M, Focaccetti C, et al. PlGF Immunological Impact during Pregnancy[J]. Int J Mol Sci, 2020, 21(22): 8714.

[6] Ichikawa G, Yamamoto T, Chishima F, et al. Effects of anti-β2-glycoprotein I antibody on PlGF, VEGF and sVEGFR1 production from cultured choriocarcinoma cell line[J]. J Obstet Gynaecol Res, 2011, 37(8): 1076-1083.

[7] Chang R, Dai J, Wang L, et al. PlGF/FLT-1 deficiency leads to reduced STAT3-C/EBPβ signaling and aberrant polarization in decidual macrophages during early spontaneous abortion[J]. Front Immunol, 2023, 14(1): 1061949.

[8] 中国医学会妇产科学分会产科学组. 复发性流产诊治的专家共识[J]. 中华妇产科杂志, 2016, 1(1): 3-9.

[9] 刘芳, 卢宗杰, 牟燕, 等. 复发性流产患者孕期D-D二聚体, 叶酸和凝血功能指标预测自然流产价值[J]. 中国计划生育学杂志, 2022, 30(12): 2840-2843.

[10] Deng T, Liao X, Zhu S. Recent Advances in Treatment of Recurrent Spontaneous Abortion[J]. Obstet Gynecol Surv, 2022, 77(6): 355-366.

[11] Xing J, Liu J, Geng T. Predictive values of sST2 and IL-33 for heart failure in patients with acute myocardial infarction[J]. Exp Biol Med (Maywood), 2021, 246(23): 2480-2486.

[12] Petramala L, Concistrè A, Sarlo F, et al. Assessment of sST2 Behaviors to Evaluate Severity/Clinical Impact of Acute Pulmonary Embolism[J]. Int J Mol Sci, 2023, 24(5): 4591.

[13] Kaitu'u-Lino TJ, Tuohey L, Tong S. Maternal serum interleukin-33 and soluble ST2 across early pregnancy, and their association with miscarriage[J]. J Reprod Immunol, 2012, 95(1-2): 46-49.

[14] Hu W T, Li M Q, Liu W, et al. IL-33 enhances proliferation and invasiveness of decidual stromal cells by up-regulation of CCL2/CCR2 via NF-κB and ERK1/2 signaling[J]. Mol Hum Reprod, 2014, 20(4): 358-372.

[15] Sheng Y R, Hu W T, Shen H H, et al. An imbalance of the IL-33/ST2-AXL-efferocytosis axis induces pregnancy loss through metabolic reprogramming of decidual macrophages[J]. Cell Mol Life Sci, 2022, 79(3): 173.

[16] Nejabati H R, Latifi Z, Ghasemnejad T, et al. Placental growth factor (PlGF) as an angiogenic/inflammatory switcher: lesson from early pregnancy losses[J]. Gynecol Endocrinol, 2017, 33(9): 668-674.

[17] Verlohren S, Brennecke SP, Galindo A, et al. Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia[J]. Pregnancy Hypertens, 2022, 27(1): 42-50.

[18] Jayasena C N, Abbara A, Comninos A N, et al. Novel circulating placental markers prokineticin-1, soluble fms-like tyrosine kinase-1, soluble endoglin and placental growth factor and association with late miscarriage[J]. Hum Reprod, 2016, 31(12): 2681-2688.

[19] Sterpu I, Anfelter P, Wray S, et al. The association of second trimester biomarkers in amniotic fluid and fetal outcome[J]. J Matern Fetal Neonatal Med, 2019, 32(21): 3627-3632.

[20] 宋姗姗, 杨洋, 陈阳, 等. 外周血miR-152, PIGF, sFlt-1和sEng水平对子痫前期患者不良孕产结局的预测分析[J]. 中国妇幼健康研究, 2022, 33(2): 45-49.

基金资助

绵阳市科技计划项目(16SG01G1)