背景:血管生成失衡,以过量的抗血管生成因子(可溶性fms样酪氨酸激酶1[sFlt-1])和减少的血管生成因子(VEGF和胎盘生长因子[PlGF])为特征,有助于先兆子痫的发病机制。sFlt-1与PlGF的比例已被用作先兆子痫的生物标志物。但截断值可能因胎龄和检测平台而异.
目的:比较母体血浆sFlt-1/PlGF比值的中位数(MoM)倍数,sFlt-1,PlGF,和常规临床和实验室值,以预测具有严重特征的子痫前期。
方法:我们在美国18个中心进行了一项队列研究,涉及妊娠23-35周的住院高血压患者。母体血浆生物标志物的受试者工作特征曲线(ROC)分析,最高的收缩压或舒张压,和纳入时的实验室值用于预测具有严重特征的先兆子痫.比较它们的曲线下面积(AUC),拟合准泊松回归模型来估计相对风险。主要结果是在入组后两周内具有严重特征的先兆子痫。次要结局是严重不良产妇结局的复合(肝酶升高,血小板计数低,胎盘早剥,子痫,弥散性血管内凝血,和肺水肿)和严重不良围产期结局的复合(出生体重<3百分位数,非常早产[<32周]和胎儿/新生儿死亡)。
结果:在纳入研究的543个人中,其中33.1%(n=180)的患者在两周内出现重度子痫前期。sFlt-1/PlGF血浆比率的ROC得出的阈值为11.5MoM,提供了灵敏度(90.6%),特异性(76.9%),阳性预测值(66.0%),阴性预测值(94.3%),正似然比(3.91),负似然比(0.12),2周内有严重特征的先兆子痫的准确性(81.4%)。该截止值用于比较测试阳性病例(≥截止值)和测试阴性病例(<截止值)。具有严重特征的先兆子痫(66.0%vs.5.7%;<0.001),和严重不良孕产妇的复合材料(8.11%vs.2.7%;p=0.006)或围产期结局(41.3%与10.14%;p=0.001)在两周内,测试阳性病例比测试阴性病例更频繁。sFlt-1/PlGF血浆比率≥11.5MoM与具有严重特征的先兆子痫(调整后的发病率比率[aIRR]:9.08,95%CI:6.11至14.06;p<0.001)和严重不良围产期结局的复合(aIRR:9.42,95%CI:6.36至14.53;p<0.001),但不包括严重不良孕产妇结局的复合(aIRR:2.20,95%CI:0.95至5.54;p=0.08)。在两周内具有严重特征的先兆子痫的MoM中sFlt-1/PlGF血浆比率的AUC(0.91;95%CI:0.89-0.94)显着高于单独的血浆生物标志物或任何其他参数。除了绝对sFlt-1/PlGF血浆比率值。
结论:住院患者SFlt-1/PlGF血浆比值≥11.5MoM,妊娠23-35周的高血压患者可预测进展为子痫前期,并在2周内出现严重特征和严重不良围产期结局.
BACKGROUND: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform.
OBJECTIVE: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features.
METHODS: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks\' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks\' gestation], and fetal or neonatal death).
RESULTS: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values.
CONCLUSIONS: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week\'s gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.