The Clinical Value of Detection of TNF-α、IL-6 and IL-17 in Premature Ruptureof Membranes with Adverse Pregnancy Outcomes Associated with Maternal and Fetal Infection
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摘要:
目的 探讨母血、脐血血清中TNF-α、IL-6、IL-17表达水平在胎膜早破（premature rupture of membranes，PROM）合并绒毛膜羊膜炎（chorioamnionitis，CS）及PROM新生儿围产期感染中的临床意义。 方法 51例因胎膜早破至昆明医科大学第一附属医院产科住院的孕妇为PROM组，同期20例正常分娩孕妇为对照组。采用ELISA法检测母血、脐血血清TNF-α、IL-6、IL-17水平。再次将PROM组分为PROM无CS组和PROM合并CS组，PROM无新生儿围产期感染组（A1）和PROM新生儿围产期感染组（A2）；比较母血、脐血中3项指标在不同分组中的表达水平，ROC曲线分析三项指标预测胎膜早破母儿感染相关不良妊娠结局的价值。 结果 （1）PROM合并CS组母血、脐血血清TNF-α、IL-6表达水平显著高于PROM无CS组和对照组（P < 0.05）；PROM无CS组母血TNF-α、脐血IL-6的表达水平显著高于对照组（P < 0.05）；（2）A2组母血、脐血血清TNF-α、IL-6和IL-17表达水平均显著高于A1组和对照组（P < 0.05）；A1组母血TNF-α、脐血IL-6的表达水平显著高于对照组（P < 0.05）；（3）母血、脐血血清TNF-α、IL-6、IL-17表达水平互呈显著正相关（P < 0.001）；（4）诊断PROM合并CS时，单项检测母血TNF-α的曲线下面积（Area under the curve，AUC）最大（0.763），母血TNF-α的AUC高于脐血TNF-α（0.614）（P < 0.05）；联合母血+脐血TNF-α+IL-6 4项指标诊断PROM合并CS的AUC（0.820）显著高于脐血TNF-α单项指标的AUC值（0.614）（P < 0.05）；（5）诊断PROM新生儿围产期感染时，单项检测时母血中IL-6的AUC最大（0.800），脐血中IL-17的AUC最大（0.829），脐血IL-17的AUC高于母血IL-17（0.735）（P < 0.05）；联合脐血IL-6+IL-17 2项指标或联合脐血TNF-α+ IL-6+ IL-17 3项指标诊断PROM发生新生儿围产期感染的诊断效果较好（AUC：0.863、0.866）。 结论 母血、脐血TNF-α、IL-6、IL-17是预测PROM母儿感染相关不良妊娠结局的重要指标，联合检测效果较好。临床工作中若考虑脐血检测的局限性，仅检测母血以上细因子也有较好的临床运用价值。 Abstract:Objective To investigate the clinical value of expression levels of TNF- α、IL-6、IL-17 in the maternal serum and umbilical cord serum in the premature rupture of membranes （PROM） with chorioamnionitis （CS） and PROM with the neonatal infection during the perinatal period. Methods 51 patients with the premature rupture of membrane who had been admitted to the Obstetrics Department of the First Affiliated Hospital of Kunming Medical University were enrolled as PROM group. At the same time, 20 normal maternities delivered in this hospital were adopted to the control group. Double antibody sandwich ELISA was used to detect the expression levels of TNF-α, IL-6 and IL-17 in the maternal serum and umbilical cord serum. After that, the PROM group was regrouped into PROM with CS group and PROM without CS group, PROM without the neonatal infection during the perinatal （group A1） and PROM with the neonatal infection during perinatal （group A2）. Comparing the expression levels of these three indicators in the maternal serum and umbilical cord serum of different groups and using ROC curve to analyze the value of these indexes above in predicting the premature ruptured of membranes with adverse pregnancy outcomes associated with maternal and fetal infection. Result （1） The levels of TNF-α and IL-6 in the maternal serum and umbilical cord serum in PROM with CS group were statistically higher than those in PROM without CS group and the control group （P < 0.05）. The levels of TNF-α in the maternal serum and the levels of IL-6 in the umbilical cord serum in the PROM without CS group were statistically higher than those in the control group （P < 0.05）. （2） Expression levels of TNF-α, IL-6 and IL-17 in the maternal serum and umbilical cord serum of A2 group were statistically higher than those of A1 group and the control group （P < 0.05）. The levels of TNF-α in the maternal serum and the levels of IL-6 in the umbilical cord serum of A1 group were significantly higher than those of the control group （P < 0.05）. （3） The expression level of TNF-α、IL-6 and IL-17 in the maternal serum and in the umbilical cord serum were significantly positively correlated （P < 0.001）. （4） In the diagnosis of PROM with CS, TNF-α in the maternal serum was of the biggest area under the curve （AUC） among all single index （0.763）. The AUC of TNF-α in the maternal serum was bigger than that in the umbilical cord serum （0.614）（P < 0.05）. When four indexes were used in combination, the AUC of TNF-α+IL-6 in the maternal serum combined with TNF-α+IL-6 in the umbilical cord serum （0.820） was bigger than that of single detection of TNF-α in the umbilical cord serum （0.614）（P < 0.05）. （5） In the diagnosis of PROM with the neonatal infection during perinatal, IL-6 was of the biggest AUC among all single index in the maternal serum （0.800） and IL-17 was of the biggest AUC among all single index in the umbilical cord serum （0.829）. The AUC of IL-17 in the umbilical cord serum was bigger than that in the maternal serum （0.735）（P < 0.05）. Two indexes combined of IL-6+ IL-17 or Three indexes combined of TNF-α+ IL-6+ IL-17 in the umbilical cord serum was of great diagnostic value （AUC: 0.863、0.866）. Conclusion TNF-α, IL-6 and IL-17 in the maternal serum and umbilical cord serum are of great predictive value for predicting PROM with CS and PROM with the neonatal infection during the perinatal period. The diagnostic value of joint detection is better. In clinical work, detection of the three indexes in the maternal serum also has a good value of the clinical application when collecting of the umbilical cord serum is limited. -
图 1 母血、脐血TNF-α、IL-6诊断PROM合并CS的ROC曲线
A：单项检测；B：联合检测。
Figure 1. ROC curve of TNF-α and IL-6 in maternal serum and umbilical cord serum in the diagnosis of PROM with CS
图 2 母血、脐血TNF-α、IL-6和IL-17诊断PROM新生儿围产期感染的ROC曲线
A：单项检测；B：联合检测。
Figure 2. ROC curve of TNF-α，IL-6 and IL-17 in maternal serum and umbilical cord serum in the diagnosis of PROM with neonatal infection during perinatal
表 1 研究对象临床资料比较（
$ \bar{x}\pm s $ ）Table 1. Comparation of clinical information between study objects （
$ \bar{x}\pm s $ ）组别 例数 产妇
年龄（岁）孕次
（次）孕前BMI
[kg/m2]孕期增重
（kg）入院体温
（℃）Apgar评分（$ \bar{x} $ ± s） 新生儿脐动脉PH值
（$ \bar{x} $ ± s）1 min 5 min 对照组 20 29.20 ± 4.82 2.45 ± 1.39 20.71 ± 2.25 12.91 ± 3.97 36.78 ± 0.38 8.95 ± 0.22 10 7.25 ± 0.07 PROM组 51 30.28 ± 3.23 2.02 ± 1.12 21.84 ± 3.26 11.79 ± 3.93 36.61 ± 0.37 9.01 ± 0.45 9.98 ± 0.14 7.26 ± 0.09 t/Z −0.919 1.354 −1.419 1.069 −1.575 −1.819 −0.623 0.316 P 0.366 0.180 0.160 0.293 0.120 0.073 0.535 0.753 
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表 2 对照组、PROM无CS组、PROM合并CS组母血、脐血各因子表达水平比较
Table 2. Comparation of various cytokine expression levels in maternal serum and umbilical cord serum between the control group，PROM without CS group and PROM with CS group
指标
（ng/L）对照组
（n = 20）PROM无CS组（n = 33） PROM合并CS（n = 18） χ2 P 母血 TNF-α 17.43（14.32，20.24） 25.40（18.57，41.54）# 48.01（28.19，302.68）#& 24.834 < 0.001 IL-6 7.00（3.56，12.40） 8.61（5.73，11.91） 15.76（8.41，62.69） #& 10.844 0.004 IL-17 48.26（32.13，64.69） 52.63（34.93，133.56） 64.99（33.27，265.14） 2.756 0.252 脐血 TNF-α 17.04（14.02，19.99） 18.25（10.86，39.21） 25.12（14.59，123.18）#& 6.285 0.043 IL-6 5.35（4.17，8.21） 8.16（5.10，17.26）# 25.37（9.43，39.33）#& 17.908 < 0.001 IL-17 33.63（17.67，45.82） 38.47（24.09，56.12） 52.93（25.62，122.31） 3.946 0.139 与对照组相比，#P < 0.05；与PROM无CS组相比，&P < 0.05。
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表 3 对照组、A1、A2组母血、脐血各因子表达水平比较
Table 3. Comparation of various cytokine expression levels in maternal serum and umbilical cord serum between the control group，A1 group and A1 group
指标（ng/L） 对照组（n = 20） A1组（n = 41） A2组（n = 10） χ2 P 母血 TNF-α 17.43（14.32，20.24） 25.40（18.57，41.54）# 48.01（28.19，302.68）#& 17.468 < 0.001 IL-6 7.00（3.56，12.40） 8.47（5.65，12.53） 47.56（10.13，148.23）#& 11.475 0.001 IL-17 48.26（32.13，64.69） 48.45（32.49，108.74） 227.41（45.31，436.34）#& 7.202 0.007 脐血 TNF-α 17.04（14.02，19.99） 18.98（11.05，32.21） 46.98（16.43，435.71）#& 6.244 0.044 IL-6 5.35（4.17，8.21） 9.14（5.38，21.64）# 33.51（17.91，94.00）#& 19.852 < 0.001 IL-17 33.63（17.67，45.82） 38.47（20.66，52.82） 91.02（50.54，365.29）#& 13.208 0.001 与对照组相比，#P < 0.05；与A1组相比，&P < 0.05。
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表 4 各细胞因子在母血、脐血中的相关性分析
Table 4. Correlation analysis of each cytokine in maternal serum with it in umbilical cord serum
项目 相关系数r P TNF-α（母血/脐血） 0.626 < 0.001* IL-6（母血/脐血） 0.646 < 0.001* IL-17（母血/脐血） 0.789 < 0.001* *P < 0.05。
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表 5 母血、脐血TNF-α、IL-6诊断PROM合并CS的ROC曲线
Table 5. ROC curve of TNF-α and IL-6 in maternal serum and umbilical cord serum in the diagnosis of PROM with CS
指标（pg/mL） 临界点 AUC 灵敏度（%） 特异度（%） 95%置信区间 P 母血 TNF-α 26.19 0.763 83.3 66.7 0.624～0.871 < 0.001 IL-6 12.32 0.702 61.1 81.8 0.558～0.822 0.013 TNF-α+ IL-6 − 0.747 77.8 66.7 0.606～0.859 0.005 脐血 TNF-α 13.52 0.614 83.3 39.4 0.468～0.747 0.1697 IL-6 11.59 0.673 72.2 66.7 0.528～0.798 0.027 TNF-α+ IL-6 − 0.628 96.4 36.4 0.481～0.759 0.115 母血+脐血 TNF-α+ IL-6 − 0.820 72.2 87.9 0.687～0.913 0.005
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表 6 母血、脐血TNF-α、IL-6和IL-17诊断PROM发生新生儿围产期感染的ROC曲线
Table 6. ROC curve of TNF-α，IL-6 and IL-17 in maternal serum and umbilical cord serum in the diagnosis of PROM with CS
指标（pg/mL） 临界点 AUC 灵敏度（%） 特异度（%） 95%置信区间 P 母血 TNF-α 26.19 0.787 90.0 56.1 0.649～0.889 < 0.001 IL-6 8.75 0.800 100 51.2 0.664～0.899 < 0.001 IL-17 179.57 0.735 60.0 85.4 0.593～0.849 0.014 TNF-α+ IL-6 − 0.810 100.0 51.2 0.675～0.906 < 0.001 TNF-α+ IL-6+ IL-17 − 0.766 90.0 61.0 0.626～0.873 0.007 脐血 TNF-α 13.52 0.722 100.0 39.0 0.579～0.838 0.015 IL-6 14.18 0.795 90 65.9 0.659～0.895 < 0.001 IL-17 53.00 0.829 80.0 78.0 0.698～0.920 < 0.001 IL-6+ IL-17 − 0.863 100.0 65.9 0.738～0.943 < 0.001 TNF-α+ IL-6+ IL-17 − 0.866 90.00 80.49 0.741～0.945 < 0.001 母血 + 脐血 TNF-α+ IL-6 +IL-17 − 0.822 90.0 75.6 0.689～0.915 < 0.001
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