Department of Obstetrics and Gynaecology, University of Cambridge; Cambridge Biomedical Research Centre, National Institute for Health and Care Research, Cambridge, United Kingdom; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Department of Obstetrics and Gynaecology, University of Cambridge; Cambridge Biomedical Research Centre, National Institute for Health and Care Research, Cambridge, United Kingdom; Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Am J Obstet Gynecol. 2023 Aug;229(2):164.e1-164.e18. doi: 10.1016/j.ajog.2023.02.001. Epub 2023 Feb 8.
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.
自发性早产是多种不同病理生理途径的终点。通过连续超声胎儿生物测量评估胎儿生长受限可预测早产和早期自发性分娩。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发性分娩，但与自发性早产的关系尚不清楚。
本研究旨在确定孕妇血清可溶性 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：胎盘生长因子比值在 20 周和 28 周时的水平，以及 20 至 28 周之间这些生物标志物的变化率是否与自发性早产的风险相关。
在英国剑桥进行的前瞻性非选择性初产妇队列研究——妊娠结局预测研究中，在 20-28 周时测量了招募的女性的母血清中的生物标志物。使用 Cox 回归和竞争风险回归评估自发性早产的风险。Cox 回归的关联通过给定生物标志物的 1 个标准差更高水平或 20 至 28 周之间标志物增加 1 个标准差的调整后的危险比进行量化。股骨长度生长缓慢是之前确定的自发性早产的危险因素，用于进行风险分层。
在 3763 名分析参与者中，95 名（2.5%）发生自发性早产，54 名（1.4%）发生医学指征性早产。在 20 周时，可溶性 fms 样酪氨酸激酶 1 和可溶性 fms 样酪氨酸激酶 1：胎盘生长因子比值较高与自发性早产风险降低相关（调整后的危险比[95%置信区间]，0.75[0.61-0.92]；P=.006 和 0.71[0.59-0.87]；P=.0009）。在 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之间没有关联，但可溶性 fms 样酪氨酸激酶 1：胎盘生长因子比值呈 U 形关系。然而，当将生物标志物量化为 20 至 28 周之间的增长率时，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：胎盘生长因子比值（1.50[1.30-1.73]；P<.0001）的自发性早产与增长率之间存在强烈的正相关，而胎盘生长因子的增长率呈负相关（0.71[0.61-0.82]；P<.0001）。在 20 至 28 周之间可溶性 fms 样酪氨酸激酶 1：胎盘生长因子比值增加最高的十分位数和股骨长度生长最慢的十分位数的女性，自发性早产的风险约为 9 倍（9.27[4.21-20.37]；P<.0001）。竞争风险回归得出了类似的结果。
可溶性 fms 样酪氨酸激酶 1 和胎盘生长因子的变化水平表明胎盘功能障碍，与自发性早产风险密切相关，尤其是与胎儿股骨长度生长缓慢相结合时。
