Chaiworapongsa Tinnakorn, Romero Roberto, Tarca Adi, Kusanovic Juan Pedro, Mittal Pooja, Kim Sun Kwon, Gotsch Francesca, Erez Offer, Vaisbuch Edi, Mazaki-Tovi Shali, Pacora Percy, Ogge Giovanna, Dong Zhong, Kim Chong Jai, Yeo Lami, Hassan Sonia S
Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, USA.
J Matern Fetal Neonatal Med. 2009 Dec;22(12):1122-39. doi: 10.3109/14767050902994838.
An imbalance between angiogenic and anti-angiogenic factors in maternal blood has been observed in several obstetrical syndromes including preeclampsia, pregnancies with fetal growth restriction and fetal death. Vascular lesions have been identified in a subset of patients with spontaneous preterm labor (PTL). It is possible that PTL may be one of the manifestations of an anti-angiogenic state. The aim of this study was to determine if patients prior to the clinical diagnosis of PTL leading to preterm delivery had plasma concentrations of angiogenic and anti-angiogenic factors different from normal pregnant women.
This longitudinal nested case-control study included normal pregnant women (n = 208) and patients with PTL leading to preterm delivery (n = 52). Maternal blood samples were collected at 6 gestational age intervals from 6 to 36.9 weeks of gestation. The end point (time of diagnosis) of the study, 'True PTL', was defined as patients presenting with PTL and delivered within 1 day. Plasma concentrations of sVEGFR-1, sVEGFR-2, sEng and PlGF were determined by ELISA. Analysis was performed with both cross-sectional and longitudinal (mixed effects model) approaches.
(1) Plasma sEng concentration in patients destined to develop PTL was higher than that in normal pregnant women from 15-20 weeks of gestation. The difference became statistical significant at 28 weeks of gestation, or approximately 5-10 weeks prior to the diagnosis of 'true PTL'. (2) Backward analysis suggests that plasma concentrations of PlGF and sVEGFR-2 were lower, and those of sVEGFR-1 were higher in patients with PTL than in normal pregnant women less than 5 weeks prior to the diagnosis of 'true PTL'; and (3) Plasma concentrations of sEng and sVEGFR-1 were higher and those of PlGF and sVEGFR-2 were lower in patients diagnosed with PTL and delivery within 1 day than in normal pregnant women who delivered at term.
The changes in sEng are demonstrable several weeks prior to the onset of preterm parturition. In contrast, the changes in the other angiogenic proteins are present close to the onset of PTL and delivery. This observation supports the view that an imbalance of angiogenic factors participates in the pathophysiology of spontaneous preterm parturition.
在包括子痫前期、胎儿生长受限妊娠和胎儿死亡在内的几种产科综合征中，已观察到母体血液中血管生成因子和抗血管生成因子之间的失衡。在一部分自发性早产（PTL）患者中已发现血管病变。PTL可能是抗血管生成状态的表现之一。本研究的目的是确定在临床诊断为导致早产的PTL之前，患者血浆中血管生成因子和抗血管生成因子的浓度是否与正常孕妇不同。
这项纵向巢式病例对照研究纳入了正常孕妇（n = 208）和导致早产的PTL患者（n = 52）。在妊娠6至36.9周期间，每隔6个孕周采集母体血样。研究的终点（诊断时间）“真正的PTL”定义为出现PTL并在1天内分娩的患者。通过酶联免疫吸附测定法（ELISA）测定血浆中可溶性血管内皮生长因子受体-1（sVEGFR-1）、可溶性血管内皮生长因子受体-2（sVEGFR-2）、可溶性内皮抑素（sEng）和胎盘生长因子（PlGF）的浓度。采用横断面和纵向（混合效应模型）方法进行分析。
（1）注定要发生PTL的患者血浆sEng浓度在妊娠15至20周时高于正常孕妇。在妊娠28周时，即“真正的PTL”诊断前约5至10周，差异具有统计学意义。（2）反向分析表明，在“真正的PTL”诊断前不到5周，PTL患者血浆PlGF和sVEGFR-2浓度较低，而sVEGFR-1浓度较高；（3）诊断为PTL并在1天内分娩的患者血浆sEng和sVEGFR-1浓度较高，而PlGF和sVEGFR-2浓度低于足月分娩的正常孕妇。
sEng的变化在早产发作前几周即可显现。相比之下，其他血管生成蛋白的变化在PTL发作和分娩临近时出现。这一观察结果支持血管生成因子失衡参与自发性早产病理生理过程的观点。
