背景:自发性早产是多种不同病理生理途径的终点。胎儿生长受限,通过连续超声胎儿生物测定法评估,已被证明可以预测早产和早期自然分娩。可溶性fms样酪氨酸激酶-1与胎盘生长因子的比值可预测早期自然分娩,但其与自发性早产的关联尚不清楚.
目的:本研究旨在确定母体血清可溶性fms样酪氨酸激酶-1,胎盘生长因子,和可溶性fms样酪氨酸激酶-1:胎盘生长因子的比例在20和28周妊娠,这些生物标志物在20-28周之间的变化率可预测自发性早产的风险。
方法:作为剑桥妊娠结局预测研究的一部分,在妊娠20周和28周的孕妇血清中测量了生物标志物,这些妇女被招募到未选择的未分娩妇女的前瞻性队列中,联合王国。使用Cox回归和竞争风险回归评估自发性早产的风险。Cox回归的关联通过在妊娠20至28周之间给定生物标志物的1个标准偏差较高水平或标志物的1个标准偏差增加的校正风险比进行量化。先前确定的风险因素,股骨长度增长缓慢,被用作自发性早产的额外预测因子,用于风险分层。
结果:在分析的3763名参与者中,95(2.5%)有自发性早产,54(1.4%)有医学指示早产。妊娠20周时,较高水平的可溶性fms样酪氨酸激酶-1和可溶性fms样酪氨酸激酶-1:胎盘生长因子比率与自发性早产风险降低相关(校正风险比[95%置信区间],0.75[0.61-0.92];P=.006和0.71[0.59-0.87];P=.0009,分别)。妊娠28周时,可溶性fms样酪氨酸激酶-1或胎盘生长因子与自发性早产风险无相关性,但与可溶性fms样酪氨酸激酶-1:胎盘生长因子比率呈U型关系。然而,当生物标志物被量化为20至28周妊娠之间的增加率时,自发性早产与可溶性fms样酪氨酸激酶-1(1.36[1.13-1.63];P=.001)和可溶性fms样酪氨酸激酶-1:胎盘生长因子比率(1.50[1.30-1.73];P<.0001)之间存在强烈的正相关,与胎盘生长因子的增加速率呈强烈负相关(0.71[0.61-0.82];P<.0001)。在妊娠20至28周之间,可溶性fms样酪氨酸激酶-1:胎盘生长因子比率增加的最高十分位数和股骨长度增长的最低十分位数的女性,其自发性早产风险约为9倍(9.27[4.21-20.37];P<.0001)。竞争风险回归产生了类似的结果。
结论:可溶性fms样酪氨酸激酶-1和胎盘生长因子水平的变化表明胎盘功能障碍,并与自发性早产的风险密切相关。特别是当与胎儿股骨长度生长较慢时。
Spontaneous preterm birth is the endpoint of multiple different pathophysiological pathways. Fetal growth restriction, assessed by serial ultrasonic fetal biometry, has been shown to predict both preterm and early-term spontaneous labor. The soluble fms-like tyrosine kinase-1 to placental growth factor ratio is predictive of early-term spontaneous labor, but its association with spontaneous preterm birth is unclear.
This study aimed to determine whether maternal serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and the soluble fms-like tyrosine kinase-1: placental growth factor ratio at 20 and 28 weeks\' gestation, and the rate of change in these biomarkers between 20 and 28 weeks were predictive of risk of spontaneous preterm birth.
The biomarkers were measured in maternal serum at 20- and 28-weeks\' gestation in women recruited to a prospective cohort of unselected nulliparous women as part of the Pregnancy Outcome Prediction study in Cambridge, United Kingdom. The risk of spontaneous preterm birth was assessed using Cox regression and competing-risks regression. Associations from Cox regression were quantified by the adjusted hazard ratio for a 1 standard deviation higher level of a given biomarker or a 1 standard deviation increase in the marker between 20 and 28 weeks\' gestation. A previously identified risk factor, slow femur length growth, was used as an additional predictor of spontaneous preterm birth for the purpose of risk stratification.
Of the 3763 participants in the analysis, 95 (2.5%) had spontaneous preterm birth and 54 (1.4%) had medically indicated preterm birth. At 20 weeks\' gestation, higher levels of soluble fms-like tyrosine kinase-1 and the soluble fms-like tyrosine kinase-1:placental growth factor ratio were associated with reduced risk of spontaneous preterm birth (adjusted hazard ratio [95% confidence interval], 0.75 [0.61-0.92]; P=.006 and 0.71 [0.59-0.87]; P=.0009, respectively). At 28 weeks\' gestation, there was no association between either soluble fms-like tyrosine kinase-1 or placental growth factor and the risk of spontaneous preterm birth, but there was a U-shaped relation with the soluble fms-like tyrosine kinase-1:placental growth factor ratio. However, when the biomarkers were quantified as the rate of increase between 20 and 28 weeks\' gestation, there were strong positive associations between spontaneous preterm birth and rate of increase in soluble fms-like tyrosine kinase-1 (1.36 [1.13-1.63]; P=.001) and the soluble fms-like tyrosine kinase-1:placental growth factor ratio (1.50 [1.30-1.73]; P<.0001), and a strong negative association with the rate of increase in placental growth factor (0.71 [0.61-0.82]; P<.0001). Women who were in the highest decile of increase in the soluble fms-like tyrosine kinase-1:placental growth factor ratio and the lowest decile of femur length growth between 20 and 28 weeks\' gestation had approximately 9-fold risk of spontaneous preterm birth (9.27 [4.21-20.37]; P<.0001). Competing-risks regression yielded similar results.
Changing levels of soluble fms-like tyrosine kinase-1 and placental growth factor are indicative of placental dysfunction and are strongly associated with the risk of spontaneous preterm birth, especially when combined with slower fetal femur length growth.