Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?
Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?
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DOI：
10.1016/j.ajog.2007.10.783
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发表时间：
2008-04-01
影响因子：
9.8
通讯作者：
Karumanchi, S. Ananth
中科院分区：
文献类型：
--
作者：
Bdolah, Yuval;Lam, Chun;Karumanchi, S. Ananth
目的：双胎妊娠是先兆子痫的危险因素，据报道其发病率比单胎妊娠高2-3倍。可溶性fms样酪氨酸激酶1（sFlt 1）是胎盘来源的循环抗血管生成分子，通过拮抗母体血管系统中的胎盘生长因子（PlGF）和血管内皮生长因子信号传导在先兆子痫中起核心作用。已显示增加的sFlt 1和sFlt 1/游离PlGF的比率先于先兆子痫的临床体征。尽管子痫前期sFlt 1表达上调的原因尚不清楚，但胎盘缺血伴缺氧被认为起重要作用。因此，我们假设，在双胞胎妊娠先兆子痫的风险较高的结果从高sFlt 1（或sFlt 1/PIGF）和sFlt 1上调是由于相对胎盘缺氧和/或胎盘质量增加。研究设计：产妇血清样本和胎盘从第三个三个月的双胞胎和单胎妊娠无先兆子痫。通过酶联免疫吸附测定分析血清样品的sFlt 1和游离PlGF水平，并报告为平均值（分别以纳克/毫升和皮克/毫升计）。取胎盘称重，用定量聚合酶链反应检测sFlt 1和PlGF信使RNA（mRNA）的含量，Western blot检测HIF-1 α蛋白表达。双胎妊娠孕妇血清中可溶性Flt 1浓度比单胎妊娠孕妇血清样品中测量的浓度高2.2倍（30.98 +/- 9.78 ng/ml）。mL vs 14.14 +/- 9.35 ng/mL; P =. 001）。游离PlGF浓度在双胎和单胎母体血清样品之间没有显著差异，但是双胎妊娠母体血清样品的平均sFlt 1/PlGF比率是单胎妊娠样品中的等效比率的2.2倍（分别为197.58 +/- 126.86 ng/mL和89.91 +/- 70.63 ng/mL; P = 0.029）。sFlt 1和PlGF mRNA的定量聚合酶链反应显示，两个研究组之间没有显着差异。胎盘样本的HIF-1 α蛋白质印迹分析显示，双胞胎与单胞胎胎盘样本的HIF-1 α/肌动蛋白的平均比值分别为0.53和0.87（双胞胎显示HIF-1 α较低，而不是较高）。双胎和单胎胎盘的平均重量分别为1246和716 g（P = .001）。重要的是，胎盘重量与循环sFlt 1水平相关性很好（R-2 = .75）。结论：在双胎妊娠中，循环sFlt 1水平和sFlt 1/PIGF比值是单胎妊娠的两倍。双胎妊娠血清sFlt 1水平升高并不伴随双胎胎盘sFlt 1 mRNA和HIF-1 α蛋白水平的任何变化，但与胎盘重量增加相关。这些发现表明，双胎妊娠中先兆子痫的风险增加可能是由于胎盘质量增加导致sFlt 1循环水平增加。
OBJECTIVE: Twin pregnancies are a risk factor for preeclampsia with a reported incidence of 2-3 times higher than singleton pregnancies. Soluble fms-like tyrosine kinase 1 (sFlt1), which is a circulating antiangiogenic molecule of placental origin, plays a central role in preeclampsia by antagonizing placental growth factor (PlGF) and vascular endothelial growth factor signaling in the maternal vasculature. Increased sFlt1 and the ratio sFlt1/free PlGF have been shown to antedate clinical signs in preeclampsia. Although the cause of the upregulated sFlt1 in preeclampsia still is not understood clearly, placental ischemia with accompanying hypoxia is thought to play an important role. We therefore hypothesized that the higher risk of preeclampsia in twin pregnancies results from high sFlt1 ( or sFlt1/PIGF) and that the sFlt1 upregulation was due to either relative placental hypoxia and/or increased placental mass.STUDY DESIGN: Maternal serum samples and placentas from third-trimester twin and singleton pregnancies without preeclampsia were used. Serum samples were analyzed for levels of sFlt1 and free PlGF by enzyme-linked immunosorbent assay and reported as means ( in nanograms per milliliter and picograms per milliliter, respectively). Placentas were weighed and examined for content of sFlt1 and PlGF messenger RNA ( mRNA) by quantitative polymerase chain reaction and hypoxia inducible factor-1 alpha(HIF-1 alpha) protein by Western blot.RESULTS: Soluble Flt1 concentrations in twin pregnancy maternal serum were 2.2 times higher than those that were measured in singleton pregnancy maternal serum samples (30.98 +/- 9.78 ng/mL vs 14.14 +/- 9.35 ng/mL, respectively; P =. 001). Free PlGF concentrations were not significantly different between twin and singleton maternal serum samples, but the mean sFlt1/PIGF ratio of twin pregnancy maternal serum samples was 2.2 times higher than the equivalent ratio in singleton pregnancy samples (197.58 +/- 126.86 ng/mL vs 89.91 +/- 70.63 ng/mL, respectively; P = .029). Quantitative polymerase chain reaction for sFlt1 and PlGF mRNA revealed no significant differences between the 2 study groups. Western blot analysis of placental samples for HIF-1 alpha revealed a mean ratio HIF1 alpha/ actin of 0.53 vs 0.87, for the twins vs singletons placental samples respectively ( twins showed lower HIF-1 alpha, not higher). The mean weights of twin and singleton placentas were 1246 vs 716 g, respectively ( P = .001). Importantly, the placental weights correlated very well with the circulating sFlt1 levels (R-2 = .75).CONCLUSION: In twin pregnancies, circulating sFlt1 levels and sFlt1/PIGF ratios were twice as high as those in singleton pregnancies. The increased serum sFlt1 levels in twin pregnancies were not accompanied by any changes in the levels of sFlt1 mRNA and HIF-1 alpha protein in the twin placentas but were correlated with increased placental weight. These findings suggest that the increased risk of preeclampsia in twin pregnancies may be due to increased placental mass that leads to increased circulating levels of sFlt1.