Supplementary Material for: Added value in low-risk pregnancies of longitudinal changes in uterine Doppler and circulating angiogenic factors during the third trimester in predicting term preeclampsia

Introduction: To assess the relationship between longitudinal changes in the uterine Doppler velocimetry and the maternal profile of angiogenic factors in the third trimester of pregnancy and to assess their ability to predict term preeclampsia. Methods: A cohort of low-risk pregnant women was constructed at second trimester routine scan and scheduled for a uterine Doppler evaluation and measurement of the circulating levels of angiogenic factors at ~30 and ~36 weeks. The performance of both parameters at both time-points and their change over time from the first to the second measurement in predicting term preeclampsia was evaluated by logistic regression and receiver operating characteristic curve (ROC) analyses. Results: A total of 1172 women were analyzed, of which 28 (2.4%) women developed term preeclampsia. At ~30 weeks, a model including the ratio sFlt-1/PlGF (fms-like tyrosine kinase-1/placental growth factor) and the uterine Doppler explained 16.2% of the uncertainty of developing term preeclampsia, while at ~36 weeks the same variables explained 25.2% [p<0.001]. A model including the longitudinal changes of both predictors had an R2 of 26.8%, which was not significantly different from that of the ~36 weeks evaluation [p=0.45]. The area under the curve (AUC) of the ~36 weeks sFlt-1/PlGF ratio was significantly higher than at ~30 weeks (0.86 [0.77-0.94] vs. 0.81 [0.73-0.9]; p=0.043). The AUC of the 30-to-36 week change of the sFlt-1/PlGF ratio (0.85 [0.77-0.94]) did not significantly differ from that of at ~36 weeks (p=0.82). At ~36 weeks, for a 10% of false positives, the sFlt-1/PlGF ratio had a detection rate of 71.4%, with positive and negative likelihood ratios of 7.3 and 0.32, respectively. Conclusion: A cross-sectional measurement of the sFlt-1/PlGF ratio outperforms uterine Doppler in predicting term preeclampsia. The combination of both markers does not improve such prediction, nor the evaluation of the longitudinal changes between ~30 and ~36 weeks.

引言：本研究旨在评估妊娠晚期子宫多普勒测速的纵向变化与母体血管生成因子谱之间的关联，并探究二者对足月子痫前期的预测效能。方法：本研究于妊娠中期常规超声检查时纳入低危妊娠妇女队列，并安排受试者在妊娠约30周及约36周时接受子宫多普勒评估及外周血血管生成因子水平检测。采用logistic回归及受试者工作特征曲线（receiver operating characteristic curve, ROC）分析，评估两个时间点的两项参数及其从首次到第二次检测的纵向变化对足月子痫前期的预测性能。结果：本研究共纳入1172名妇女进行分析，其中28名（2.4%）发生足月子痫前期。在妊娠约30周时，纳入可溶性fms样酪氨酸激酶1/胎盘生长因子（sFlt-1/PlGF）比值与子宫多普勒指标的模型可解释16.2%的足月子痫前期发病不确定性；而在妊娠约36周时，相同变量可解释25.2%的不确定性（p<0.001）。纳入两项预测指标纵向变化的模型的决定系数R²为26.8%，与妊娠约36周时的评估结果无显著差异（p=0.45）。妊娠约36周时sFlt-1/PlGF比值的受试者工作特征曲线下面积（area under the curve, AUC）显著高于妊娠约30周时（0.86 [95%置信区间: 0.77-0.94] vs. 0.81 [95%置信区间: 0.73-0.90]；p=0.043）。妊娠30至36周间sFlt-1/PlGF比值变化的AUC为0.85 [95%置信区间: 0.77-0.94]，与妊娠约36周时的检测结果无显著差异（p=0.82）。在妊娠约36周时，当假阳性率为10%时，sFlt-1/PlGF比值的检出率为71.4%，其阳性似然比与阴性似然比分别为7.3和0.32。结论：单次检测sFlt-1/PlGF比值在预测足月子痫前期方面的效能优于子宫多普勒检测。联合两项指标并不能提升该预测效能，同样，评估妊娠约30周至约36周间的纵向变化也无法改善预测效果。