循环血管生成因子与子痫前期风险

Circulating angiogenic factors and the risk of preeclampsia.

作者信息

Levine Richard J, Maynard Sharon E, Qian Cong, Lim Kee-Hak, England Lucinda J, Yu Kai F, Schisterman Enrique F, Thadhani Ravi, Sachs Benjamin P, Epstein Franklin H, Sibai Baha M, Sukhatme Vikas P, Karumanchi S Ananth

机构信息

Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, Department of Health and Human Services, Bethesda, MD 20892, USA.

出版信息

N Engl J Med. 2004 Feb 12;350(7):672-83. doi: 10.1056/NEJMoa031884. Epub 2004 Feb 5.

DOI:10.1056/NEJMoa031884

PMID:14764923

Abstract

BACKGROUND

The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role.

METHODS

We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia.

RESULTS

During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant.

CONCLUSIONS

Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia.

摘要

背景

子痫前期的病因仍不清楚。有限的数据表明，循环中过量的可溶性fms样酪氨酸激酶1（sFlt-1）可结合胎盘生长因子（PlGF）和血管内皮生长因子（VEGF），可能具有致病作用。

方法

我们在预防子痫前期的钙补充试验中进行了一项巢式病例对照研究，该试验纳入了健康的未生育女性。每例子痫前期患者与一名血压正常的对照者匹配。总共随机选取了120对女性。在整个孕期测量血管生成因子（总sFlt-1、游离PlGF和游离VEGF）的血清浓度；共有655份血清标本。在孕周区间内并根据子痫前期发病前的时间对数据进行横断面分析。

结果

在血压正常的对照者孕期的最后两个月，sFlt-1水平升高而PlGF水平降低。这些变化在后来发生子痫前期的女性中出现得更早且更明显。sFlt-1水平在子痫前期发病前约五周开始升高。在临床疾病发作时，子痫前期女性的平均血清水平为每毫升4382皮克，而孕周相似的对照者胎儿的血清水平为每毫升1643皮克（P<0.001）。从妊娠13至16周开始，后来发生子痫前期的女性的PlGF水平显著低于对照者（平均为每毫升90皮克对每毫升142皮克，P=0.01），在子痫前期发病前的几周差异最大，与sFlt-1水平的升高同时出现。子痫前期发病较早的女性以及子痫前期与小于胎龄儿相关的女性中，sFlt-1和游离PlGF水平的变化更大。