sFlt-1/PlGF 值在预测子痫前期及孕妇结局中的临床研究
张亚凤1 郑仙芝2 薛玲娜3 党媛翟4 翟芬菊4△
(1 咸阳市彩虹医院 陕西 咸阳 712000 中国;2 韩城市妇幼保健院 陕西 渭南 705405 中国;3 韩城市人民医院 陕西 渭南 715400 中国;4 渭南市第一医院 陕西 渭南714000 中国;)
摘要 目的:本研究主要探究可溶性络氨酸激酶受体1和胎盘生长因子其比值(sFlt-1/PlGF)在子痫前期发病的诊断效能及孕妇结局的作用。方法:研究收集2011-2014年间有子痫前期征兆的妊娠期受试者180例,根据结局,发展为子痫前期患者为实验组(n = 84),未发展为子痫前期患者为对照组(n = 96),分别测定了受试者收缩压、舒张压、尿蛋白浓度、血浆可溶性血管内皮生长因子受体1浓度,胎盘生长因子浓度等指标,以探讨其影响。结果:实验组和对照组患者的妊娠期(t=2.381,P=0.020)、收缩压(t=5.387,P<0.001)、舒张压(t=3.581,P<0.001)以及尿蛋白浓度(t=4.962,P<0.001)存在显著性统计差异。sFlt-1\PIGF值的ROC曲线下的面积值AUG为0.90,其95%置信区间为0.425-1.527,其截断值为85,sFlt-1\PIGF值的敏感度和特异度为91%和89%。实验组和对照组两组患者的sFlt-1\PIGF值(t=2.404,P=0.018)存在显著统计学差异。对于妊娠期<34周的受试者,实验组和对照组两组患者间存在极显著统计差异(t=3.426,P=0.001)。在34周内,sFlt-1/PIGF≥85组78.3%受试者未分娩,sFlt-1/PIGF<85组仅21.4%的受试者未分娩,且两组存在(χ2=8.952,P=0.003)统计学差异。结论:血清sFlt-1/PIGF比值是子痫前期高危患者的子痫前期的诊断和预后的有效标志物,尤其是血清sFlt-1/PIGF≥85的子痫前期高危患者具有更高的子痫前期发病率。
关键词:可溶性血管内皮生长因子受体1;子痫前期高危人群;妊娠期;胎盘生长因子
Predictive value oftheratio SFlt-1 and PlGF in the prediction of preeclampsia and outcome in clinical studies
ZHANG YA-Feng1, ZHENG Xian- Zhi2, XUE Ling-Na3, DANG Yuan-Zhai4, ZHAI Fen- Ju4△
(1 rainbow Hospital of Xianyang, Xianyang, Shaanxi, 712000, China ;2 Hancheng maternal and child health care hospital, Weinan, Shaanxi, 705405, China; 3 Hancheng People's Hospital, Weinan Shaanxi, 715400, China; 4 Weinan First Hospital, Weinan, shaanxi, 714000, China)
ABSTRACT Objective :The study mainly described the effect of the ratio of SFlt-1 and PlGF on preeclampsia patients and preeclampsia in high-risk patients, to analysis the predictive value of the ratio of SFlt-1 and PlGF for preeclampsia.Methods:Our study collected 180preeclampsia in high-risk patientsbetween 2011-2014, divided into experimental group (n = 38) and control group group ( n = 32), and measured systolic blood pressure, diastolic blood pressure, Uric acid in triage, sFlt-1 and PIGF, to analysis the effect. Results:The experimental group and control group in trimester of pregnancy (t=2.381,P=0.020), systolic blood pressure (t=5.387,P<0.001), diastolic blood pressure (t=3.581,P<0.001) and urinary protein concentration (t=4.962,P<0.001) have significantly statistical differences.The ROC curve of ratio SFlt-1 and PlGF under AUG is 0.90, the 95% confidence interval is from 0.425 to 1.527, the cutoff value is 85, the sensitivity and specificity ofthe ratio SFlt-1 and PlGF is 91% and 89%. The ratio SFlt-1 and PlGF in experimental group and control group is (t=2.404,P=0.018) statistically significant differences.For pregnancy < 34 weeks of subjects, the experimental group and the control group significantly statistical differencesin the ratio SFlt-1 and PlGF between the two groups of patients (t=3.426,P=0.001).after 34 weeks,78.3% of the subjects who have the ratio SFlt-1 and PlGF ≥85% are not deliver, and for the ratio SFlt-1 and PlGF< 85 patients only 21.4% of the subjects are not deliver, which hasstatisticallydifferencesin the two groups (χ2=8.952,P=0.003).Conclusion: The ratio of sFlt-1 and PIGF in patients at high risk of preeclampsia is effective markers for the diagnosis and prognosis of preeclampsia. Especially the ratio of sFlt-1 and PIGF is 85 or more in patients at high risk of preeclampsia patients have a higher incidence of preeclampsia.
Key words:Soluble fms-like tyrosine kinase 1; Preeclampsia in high-risk patients; trimester of pregnancy; Proangiogenic placental grow factor
子痫前期(Preeclampsia,PE)是女性妊娠期间的一大障碍[1]。严重威胁母体和新生儿的健康,在一般孕妇的发病率在5%-10%,而在高危险性孕妇病发率高达10%-25%。根据世界卫生组织的报告,每年有超过100000人因此而死亡,在发展中国家居多[2]。因此,准确预测子痫前期对于妊娠期孕妇非常重要[3,4],从而提供适当的产前预防和治疗。目前,对子痫前期的发病机理仍未明确,主要认为胎盘滋养细胞侵入母体子宫螺旋动脉时出现问题,导致胎盘浅着床,进而导致胎盘发育过程出现不良状况,而胎盘的细胞因子是影响胎盘正常发育的重要因素,血管生成因子与其受体含量的平衡对于胎盘血管床的正常发育具有关键作用,两者间比值异常是子痫前期发病的重要因素,且具有较高的灵敏度[5]。研究发现,在子痫前期发病之前,等胎盘的细胞因子血清水平发生变化,是早期预测和诊断子痫前期的有效标志物。Wa Law等[6]对中国女性进行临床研究,妊娠早期血清胎盘生长因子(Proangiogenic placental grow factor,PIGF)水平较低的妊娠期孕妇发展为子痫前期的比例显著较高,但血清可溶性络氨酸激酶受体1(Soluble fms-like tyrosine kinase 1,sFlt1-1)的水平无统计学意义。目前为止,还没有对中国子痫前期高危人群妊娠期进行实证研究,评估sFlt-1/PIGF值在子痫前期的诊断效能。
1 材料与方法
1.1 资料来源
本研究选取并调查了2011年2月至2014年6月有子痫前期征兆的受试者。纳入标准:选取我院妇产科13-34周妊娠期的孕妇,满足高血压、既往子痫前期病史、子痫前期家族史、孕产次>1、年龄<18岁或年龄>40岁、糖尿病等条件之一,基于排除标准筛选,排除标准:孕妇具有心脏病,羊水过少,中风以及肾脏失调等症状。共计180例患者符合纳入标准。发展为子痫前期患者为实验组,未发展为子痫前期患者为对照组,实验组84例,对照组96例。所有研究对象均签署书面知情同意书,并获得医院伦理道德委员会的批准,所有数据只用于科学研究。
1.2 测量标准
记录所有符合纳入标准孕妇的年龄,妊娠期,子痫前期家族病史,孕妇是否具有子痫前期病史,孕妇的血压(妊娠期16周后每月测量一次,每次测量两次,间隔6h,取平均值)和尿蛋白(妊娠期16周后每月测量一次)等。所有受试者在签署同意后第二日早晨空腹抽取静脉血8ml,离心后取血清置于-80℃冷藏,严格按照酶联免疫分析法检测受试者血清sFlt-1,PIGF水平。在妊娠期间高血压140/90mm汞柱以上, 24小时尿液样本中蛋白质大于300mg,则诊断为子痫前期。
1.3 统计学分析
所有数据均用SPSS 16.0软件进行统计分析,在Origin9完成图表制作,文中计量数据以平均值 ± SD表示,分类数据以%表示。基线特征分类变量的显著性运用χ2检验,正态分布的连续变量运用t检验,对于不符合正态分布的数据,本研究采用自然对数转后后进行分析。ROC曲线和Kaplan-Meier生存分析sFlt-1\PIGF对受试者子痫前期发病率以及妊娠结局的差异,P < 0.05被认为具有统计学意义。
2 结果与分析
2.1 受试者人口学特征分析
研究表明,实验组和对照组患者在年龄(t=0.837,P=0.405)、BMI(t=1.063,P=0.291)、孕产次(χ2=0.101,P=0.865)、子痫前期病史(χ2=0.211,P=0.695)、糖尿病人数(χ2=0.526,P=0.496)等方面均无显著性差异(P> 0.05)。但两组患者的妊娠期(t=2.381,P=0.020)、收缩压(t=5.387,P<0.001)、舒张压(t=3.581,P<0.001)以及尿蛋白浓度(t=4.962,P<0.001)存在显著性差异。
表1 研究对象的一般情况对比分析
Tab 1 Compared of the different between the research object characteristic
Independent variable |
Test group(n=84) |
Control group(n=96) |
t / χ2 |
P Value |
Age (years) |
29.71±2.73 |
28.52±2.48 |
0.837 |
0.405 |
Pregnancy (weeks) |
37.42±1.25 |
35.23±1.03 |
2.381 |
0.020 |
Pregnancy ≥34 weeks |
70(83.33%) |
23(23.96%) |
63.245 |
<0.001 |
Pregnancy <34 weeks |
14(16.67%) |
73(76.04%) |
BMI(kg/m2) |
29.18±2.12 |
28.84±2.37 |
1.063 |
0.291 |
Pregnancy times ≤1 |
63(75.00%) |
70(72.92%) |
0.101 |
0.865 |
Pregnancy> 1 |
21(25.00%) |
26(27.08%) |
Preeclampsia history(a) |
38(45.24%) |
49(51.04%) |
0.211 |
0.695 |
diabetes |
17(20.24%) |
25(26.04%) |
0.526 |
0.496 |
Systolic blood pressure(mmHg) |
149±5.49 |
123±9.37 |
5.387 |
<0.001 |
Diastolic blood pressure(mmHg) |
91±4.83 |
86±4.18 |
3.581 |
<0.001 |
Urine protein(umol/L) |
311±10.58 |
246±11.26 |
4.962 |
<0.001 |
Note: a, preeclampsia history, including patients with preeclampsia history and family history of preeclampsia; P <0.05 for the difference was statistically significant.
2.2 SBP、尿蛋白和sFlt-1\PIGF值对子痫前期的诊断效能分析
利用ROS曲线(受试者工作特征曲线),评估收缩压SBP、尿蛋白以及sFlt-1\PIGF值在子痫前期的诊断效能。由图1可知,SBP的ROC曲线下的面积值AUG为0.78,其95%置信区间为0.217-0.932。SBP测定的敏感度和特异度为81%和86%。尿蛋白的ROC曲线下的面积值AUG为0.82,其95%置信区间为0.362-1.027。尿蛋白测定的敏感度和特异度为89%和71%。sFlt-1\PIGF值的ROC曲线下的面积值AUG为0.90,其95%置信区间为0.425-1.527其截断值为85,sFlt-1\PIGF值的敏感度和特异度为91%和89%。
图1 SBP、尿蛋白和sFlt-1\PIGF值对子痫前期预测的ROC曲线
Fig. 1 ROC curve of PLR, NLR and CRP for predict PE
2.3 实验组与对照组sFlt-1\PIGF值差异分析
研究结果图2A显示,对于实验组和对照组两组患者的sFlt-1\PIGF值(t=2.404,P=0.018)存在显著统计学差异。根据sFlt-1\PIGF预测ROC曲线,其截断值为85,图2B显示对于妊娠期<34周受试者,实验组和对照组患者两组患者间存在极显著差异(t=3.426,P=0.001)。
图2.受试者实验组和对照组sFlt-1\PIGF值差异
Figure 2.The difference of the indexes of sFlt-1\PIGFin two groups
Note: Figure A is for all subjects, the development of preeclampsia for the experimental group, not developed for the preeclampsia patients as the control group, Figure B is the 34 weeks of pregnancy subjects, the development of preeclampsia patients (In85 = 4.44), after the normal distribution, the independent samples were used for T test, and the difference between the experimental group and the control group was significant (P <0.05).
2.2.3 受试者分娩概率Kaplan-Meier生存分析
根据血清sFlt/PIGF值将受试者分为sFlt-1/PIGF<85和sFlt-1/PIGF≥85两组,利用Kaplan-Meier生存分析受试者在34周后未分娩的概率。结果显示,在34周内,sFlt-1/PIGF≥85组78.3%受试者未分娩,sFlt-1/PIGF<85组仅21.4%的受试者未分娩,Log Rank(Mantel-Cox)整体比较显示两组存在(χ2=8.952,P=0.003)统计学差异。
图3.基于Kaplan-Meier生存分析sFlt-1/PIGF值对分娩的影响
Figure 3.Kaplan-Meier survival for time to delivery for sFlt-1/PIGF
Note: The abscissa is based on 32 weeks as the starting point, indicating that on the basis of the 32-week period, the rate of non-delivery changes.
3 讨论与结论
之前研究显示,孕妇在发生子痫前期之前血清sFlt-1和PIGF浓度会有不同程度的升高[7],但对于sFlt-1/PIGF浓度比值与子痫前期发病的相关性研究很少,本研究讨论妊娠期具子痫前期征兆受试者的sFlt-1/PIGF浓度比值在子痫前期及结局预测中的效能,结果显示,血清sFlt-1/PIGF对子痫前期的诊断和预后是一个有效的标志物。这与之前的研究相似[7]。血清sFlt-1/PIGF对于患者的子痫前期的诊断和预后高于血压或尿蛋白,血清sFlt-1/PIGF≥85%的患者子痫前期发病率较高,但妊娠期<34周的子痫前期高危患者人数比例,sFlt-1/PIGF<85%的患者的显著大于sFlt-1/PIGF≥85%的患者。
我们研究结果显示,相较于血压和尿蛋白,血清sFlt-1/PIGF的AUG值最大,其特异性和敏感度为,这与之前的研究相似[8,9],高浓度水平的sFlt-1,或者PIGF水平浓度较低,与子痫前期的发病率具有高的正相关作用。研究表明,相较于整体受试者,对于妊娠期期<34周的患者,血清sFlt-1/PIGF的预测精准度最高。可能部分原因[10-12]是由于对于妊娠期孕妇,在妊娠36周左右,血清sFlt-1/PIGF值将会升高,因此血清sFlt-1/PIGF在妊娠后期确诊子痫前期。但是,由于大部分患者的子痫前期发病时期在妊娠34周前[13-15],因此血清sFlt-1/PIGF对于子痫前期高危患者诊断不会产生干扰作用。
其次,目前对于子痫前期的诊断[16-18],由于要测定血压和24小时尿蛋白含量,一般需要住院或者多次到医院检查,血清sFlt-1/PIGF诊断子痫前期相对较为简单,而且诊断效能较高,尤其是对于妊娠期<34周患者。但是根据之前的研究结果[19-20],血清sFlt-1含量和PIGF含量对于严重脂肪肝患者、羊水过少患者的无法进行诊断,这可能由于患者并发症导致体内sFlt-1含量和PIGF含量产生变化,因此本研究排除了此类并发症患者。
本研究还存在一些不足的地方。首先,血清sFlt-1/PIGF的采样时间,本研究没有对妊娠期子痫前期高危患者的采样时间进行统计分类,因此没有详细对不同妊娠时间的患者血清sFlt-1/PIGF值进行讨论比较。其次,由于条件限制,对子痫前期患者没有进行跟踪调查研究,对新手儿的结局也没有进行进一步研究。
综上所述,研究发现血清sFlt-1/PIGF是子痫前期高危患者的子痫前期的诊断和预后的有效诊断标志物,尤其是血清sFlt-1/PIGF≥85%的子痫前期高危患者具有更高的子痫前期发病率,且妊娠期较sFlt-1/PIGF<85%的患者长。
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作者简介:张亚凤(1971-),女,学士,副主任医师,主要研究方向:妇产科常见疾病的争端治疗
△通讯作者:翟芬菊(1973--),女,学士,副主任医师,主要研究方向:常见妇科疾病的应用研究,E-mail::scholary @163.com。电话:15399424726.
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