孕妇外周血浆中高甲基化RASSF-1A基因水平与自然流产的关系研究

Correlation of maternal plasma hypermethylated RASSF1A levels with short term outcome of first-trimester threatened abortion

目的通过检测孕早期发生先兆流产孕妇血浆中高甲基化RASSF-1A水平,并随访早期妊娠结局,评估利用孕妇血浆中高甲基化RASSF-1A预测孕早期出现先兆流产的孕妇发生自然流产的临床价值。方法该研究是一项前瞻性研究,最终共有孕早期(6～11.6周)孕妇1767名,根据妊娠结局分为三组:自然流产组(A组)、先兆流产但妊娠结局正常组(B组)、正常对照组(C组)。高甲基化RASSF-1A基因用来代表胎儿DNA,应用实时定量PCR方法检测上述各实验组孕妇血浆胎儿DNA的含量。结果正常孕妇在孕早期血浆中的高甲基化RASSF-1A水平随着孕周的增长而增高;自然流产组孕妇血浆高甲基化RASSF-1A的中位数倍值是正常对照组的4.64倍,有统计学差异(P<0.01),而在有先兆流产但妊娠结局正常组与正常对照组之间无统计学差异(P>0.05);若用高甲基化RASSF-1A的4.92MoMs来预测自然流产,灵敏度为98.2%,假阳性率为1.8%,特异度为91.2%。结论对于发生先兆流产的孕妇,尤其在孕早期,孕妇血浆中的甲基化RASSF-1具有预测自然流产的临床价值,有望成为临床上预测有先兆流产症状的孕妇孕早期发生自然流产新的生物学指标。

Objective Our objectives were to determine whether maternal plasma fetal DNA （hypcrmethylated RASSF 1 A） levels could be used to predict the subsequent outcome of women who had vaginal bleeding in the first trimester. Methods We prospectively studied pregnant women who presented with vaginal bleeding in the first trimester of pregnant, and those who had no vaginal bleeding （controls）. Hypermethylated RASSF1A was used to measure the maternal plasma levels of fetal DNA respectively by real-time PCR. Results A total of 1767 women were studied. Fetal DNA concentrations increased with gestation from 6 to 11.6 weeks in the controls. The multiple of medians （MoMs） of hypermethylated RASSF1A concentration in those who miscarried were significantly greater （P〈0.01） than the normal controls by about 4.64 folds respectively. Using a cut-off value of 4.92 MoMs for hypermethylated RASSF1A to predict miscarriage, the sensitivity was 98.2% and false positive rate was 1.8% and the specificity was 91.2%. Conclusion Maternal plasma hypermethylated RASSF1A concentrations increased throughout the first trimester. Significantly high levels of hypermethylated RASSF1A was found in those who miscarried. And hypermethylated RASSF1A inmaternal plasma was informative to predict the outcome of first trimester threathened abortion.