Jayasena C N, Abbara A, Comninos A N, Narayanaswamy S, Gonzalez Maffe J, Izzi-Engbeaya C, Oldham J, Lee T T M, Sarang Z, Malik Z, Dhanjal M K, Williamson C, Regan L, Bloom S R, Dhillo W S
Section of Investigative Medicine, Imperial College London, W12 0NN, UK.
Imperial Clinical Trials Unit, Imperial College London, SW7 2AZ, London, UK.
Hum Reprod. 2016 Dec;31(12):2681-2688. doi: 10.1093/humrep/dew225. Epub 2016 Sep 22.
Are novel circulating placental markers prokineticin-1 (PK-1), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) associated with late miscarriage in asymptomatic first trimester pregnant women?
Increased serum sFlt-1 or PlGF, but not sEng or PK-1, were significantly associated with reduced miscarriage risk after adjustment for age, BMI, gestational age, smoking and blood pressure.
Abnormal placental development is observed in two-thirds of miscarriages. Identifying women at high risk of late miscarriage could help diagnose potentially treatable causes of miscarriage such as infection, thrombosis or immunological disease. Recently, the circulating placental markers PK-1, sFlt-1, sEng and PlGF have been identified; however, it is not known if circulating levels of these markers are associated with late miscarriage.
STUDY DESIGN, SIZE, DURATION: A single-centre observational cohort study with prospectively collected data was carried out at a tertiary care centre 2010-2012, in 993 asymptomatic pregnant women. Plasma PK-1, and serum sEng, sFlt-1 and PlGF were measured once in each patient during the antenatal booking visit, and pregnancy outcome was monitored prospectively. Less than 1% of patients were lost to follow-up. Multiples of median (MOM) levels were calculated to adjust for gestational age.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine-hundred and ninety-three asymptomatic pregnant women attending antenatal clinic for a routine booking antenatal appointment were recruited to the study, of whom 12 were lost to follow-up and excluded from analysis. Of the cohort, 50 of the remaining 981 women suffered late miscarriage.
Gestation-adjusted sEng, sFlt-1 and PlGF levels were 11% (P < 0.01), 36% (P < 0.001) and 30% (P < 0.001), respectively, lower in women who later suffered miscarriage compared with unaffected pregnancies, while PK-1 did not differ significantly. Logistic regression modelling suggested that increased sFlt-1 (odds ratio (OR) 0.15 95% confidence interval [0.08-0.26], P = 0.0001) and PlGF (OR 0.02 [0.01-0.05], P = 0.0001), but not sEng, were associated with reduced miscarriage risk after adjustment for age, BMI, gestational age, smoking and blood pressure. The combination of sFlt-1 and PlGF did not improve the diagnostic accuracy beyond the use of sFlt-1.
LIMITATIONS, REASONS FOR CAUTION: First trimester levels of sFlt-1 and PlGF, but not sEng or PK-1, were associated with late miscarriage risk in asymptomatic women. However, a new prospective study is now required to investigate the utility of these markers to predict early (<10 weeks) and late miscarriage, as well as to predict other complications of pregnancy.
Our data suggest that circulating sFlt-1 and PlGF, but not sEng or PK-1, are independently associated with late miscarriage risk in asymptomatic pregnant women attending their antenatal visit. Therefore, sFlt-1 and PlGF may represent novel markers of placental viability. These data further our understanding of placental function, and have important potential implications for utilizing novel hormonal markers to detect adverse clinical outcomes during pregnancy.
STUDY FUNDING/COMPETING INTERESTS: The authors have no competing interests. The Section of Investigative Medicine is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme. This project was funded by an NIHR grant (reference: CDF-2009-02-05). The following authors are also funded as follows: CNJ is supported by an NIHR Clinical Lectureship and AMS/ Wellcome Starter Grant for Clinical Lecturers. AA and ANC are supported by NIHR academic clinical lectureships. CI-E is supported by an Imperial College Healthcare NHS Trust Charity Research Fellowship. WSD is supported by an NIHR Career Development Fellowship.
Q0406/80.
新型循环胎盘标志物促动力蛋白-1（PK-1）、可溶性fms样酪氨酸激酶-1（sFlt-1）、可溶性内皮糖蛋白（sEng）和胎盘生长因子（PlGF）与无症状孕早期孕妇晚期流产是否相关？
在对年龄、体重指数、孕周、吸烟和血压进行校正后，血清sFlt-1或PlGF升高与流产风险降低显著相关，而sEng或PK-1则不然。
三分之二的流产病例存在胎盘发育异常。识别晚期流产高危女性有助于诊断潜在可治疗的流产原因，如感染、血栓形成或免疫性疾病。最近，已鉴定出循环胎盘标志物PK-1、sFlt-1、sEng和PlGF；然而，尚不清楚这些标志物的循环水平是否与晚期流产相关。
研究设计、规模、持续时间：2010年至2012年在一家三级医疗中心对993例无症状孕妇进行了一项单中心观察性队列研究，前瞻性收集数据。在产前初诊时对每位患者测量一次血浆PK-1以及血清sEng、sFlt-1和PlGF，并对妊娠结局进行前瞻性监测。失访患者不到1%。计算中位数倍数（MOM）水平以校正孕周。
研究对象/材料、地点、方法：招募993例到产前门诊进行常规初诊的无症状孕妇参与本研究，其中12例失访，被排除在分析之外。在其余981例女性中，有50例发生晚期流产。
与未流产的妊娠相比，发生流产的女性经孕周校正后的sEng、sFlt-1和PlGF水平分别低11%（P<0.01）、36%（P<0.001）和30%（P<0.001），而PK-1无显著差异。逻辑回归模型显示，在对年龄、体重指数、孕周、吸烟和血压进行校正后，sFlt-1升高（比值比（OR）0.15，95%置信区间[0.08 - 0.26]，P = 0.0001）和PlGF升高（OR 0.02[0.01 - 0.05]，P = 0.0001）与流产风险降低相关，而sEng则不然。sFlt-1和PlGF联合使用并未比单独使用sFlt-1提高诊断准确性。
局限性、谨慎理由：孕早期sFlt-1和PlGF水平，而非sEng或PK-1水平，与无症状女性的晚期流产风险相关。然而，现在需要一项新的前瞻性研究来调查这些标志物预测早期（<10周）和晚期流产以及预测妊娠其他并发症的效用。
我们的数据表明，循环sFlt-1和PlGF，而非sEng或PK-1，与前来产前检查的无症状孕妇的晚期流产风险独立相关。因此，sFlt-1和PlGF可能代表胎盘活力的新型标志物。这些数据加深了我们对胎盘功能的理解，并对利用新型激素标志物检测妊娠期间不良临床结局具有重要潜在意义。
研究资金/利益冲突：作者无利益冲突。调查医学科由医学研究委员会（MRC）、生物技术与生物科学研究委员会（BBSRC）、国家卫生研究院（NIHR）的资助、一项综合哺乳动物生物学（IMB）能力建设奖、一项FP7 - HEALTH - 2009 - 241592欧洲芯片资助以及NIHR帝国生物医学研究中心资助计划提供资金支持。本项目由NIHR资助（参考文献：CDF - 2009 - 02 - 05）。以下作者也获得了相应资助：CNJ由NIHR临床讲师职位以及AMS/惠康临床讲师启动资助提供支持。AA和ANC由NIHR学术临床讲师职位提供支持。CI - E由帝国学院医疗保健国民保健服务信托慈善研究奖学金提供支持。WSD由NIHR职业发展奖学金提供支持。
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