基于sFlt-1/PlGF构建预测双胎妊娠子痫前期发生的风险模型

目的 构建可溶性血管内皮生长因子受体1（sFlt-1）/胎盘生长因子（PlGF）预测双胎妊娠子痫前期发生的风险模型。方法 选取2018年12月—2021年6月在海南西部中心医院和儋州市人民医院就诊的双胎妊娠孕妇216例，根据是否发生子痫前期将其分为正常组（170例）、子痫前期组（46例），根据子痫前期发生时间将子痫前期组分为早发型子痫前期组（21例）、晚发型子痫前期组（25例）。比较正常组、早发型子痫前期组、晚发型子痫前期组不同妊娠时期血清sFlt-1/PlGF；比较正常组、子痫前期组临床资料及sFlt-1/PlGF；采用逐步多因素Cox风险比例回归模型分析双胎妊娠孕妇发生子痫前期的危险因素，构建双胎妊娠孕妇发生子痫前期的指数方程，并采用受试者工作特征（ROC）曲线评估预测模型对子痫前期的预测价值。结果 正常组、早发型子痫前期组、晚发型子痫前期组12～14周、20～24周、28～32周血清sFlt-1/PlGF比较，采用重复测量设计的方差分析，结果 ①不同时间点血清sFlt-1/PlGF有差异（F =385.642，P =0.000）；②3组孕妇血清sFlt-1/PlGF有差异（F =267.241，P =0.000），早发型子痫前期组血清sFlt-1/PlGF较高；③3组孕妇血清sFlt-1/PlGF变化趋势有差异（F =342.524，P =0.000）。与正常组比较，子痫前期组孕前BMI、高血压占比、MAP、PI及20～24周、28～32周血清sFlt-1/PlGF升高（P <0.05）。逐步多因素Cox风险比例回归模型分析结果显示，高血压［H^R=2.963（95% CI：1.854，2.939）］，以及孕前BMI［H^R=3.662（95% CI：2.104，5.220）］、MAP［H^R=3.515（95% CI：1.523，5.507）］、PI［H^R=2.683（95% CI：1.359，4.007）］、20～24周血清sFlt-1/PlGF［H^R=4.674（95% CI：2.379，6.969）］、28～32周血清sFlt-1/PlGF高［H^R=3.706（95% CI：1.654，5.758）］是双胎妊娠孕妇发生子痫前期的危险因素（P <0.05）。双胎妊娠孕妇发生子痫前期的指数方程为PI=0.412X₁+0.579X₂+0.485X₃+0.418X₄+0.167X₅+0.879X₆，AUC为0.861（95% CI：0.752，0.970），敏感性为0.922（95% CI：0.887，0.957），特异性为0.863（95% CI：0.785，0.941），约登指数为0.785。结论 孕20～24周、28～32周血清sFlt-1/PlGF高是双胎妊娠孕妇发生子痫前期的危险因素，妊娠中后期监测该指标可有效预测双胎妊娠子痫前期。

Development of a risk model for predicting the occurrence of preeclampsia in twin pregnancy based on sFlt-1/PlGF levels

Objective To develop a risk model for predicting the occurrence of preeclampsia in twin pregnancy based on the levels of soluble fms-like tyrosine kinase-1 (sFlt-1) / placental growth factor (PlGF).Methods A total of 216 women with twin pregnancy who were admitted to and treated in our hospital and Danzhou People''s Hospital from December 2018 to June 2021 were selected, and they were divided into normal group (n = 170) and preeclampsia group (n = 46) according to whether preeclampsia occurred or not. Furthermore, preeclampsia group was subdivided into early-onset preeclampsia group (n = 21) and late-onset preeclampsia group (n = 25) according to the occurrence time of preeclampsia. The serum sFlt-1/PlGF levels in normal group, early-onset preeclampsia group and late-onset preeclampsia group at different pregnancy stages were compared. The clinical data and sFlt-1/PlGF levels between normal group and preeclampsia group were compared. The Cox proportional-hazards model was used to analyze the risk factors of preeclampsia in women with twin pregnancy. The equation of the Cox regression for preeclampsia in women with twin pregnancy was constructed, and the receiver operating characteristic (ROC) curve was used to evaluate the predictive value of the risk model.Results The serum levels of sFlt-1/PlGF were compared among the groups at 12 to 14 weeks, 20 to 24 weeks, and 28 to 32 weeks of gestation via repeated measures ANOVA. The results revealed that the serum levels of sFlt-1/PlGF were different among the time points (F = 385.642, P = 0.000) and among the three groups (F = 267.241, P = 0.000). Specifically, the serum levels of sFlt-1/PlGF were higher in the early-onset preeclampsia group (P < 0.05). Besides, the change trends of serum levels of sFlt-1/PlGF were also different among the groups (F = 342.524, P = 0.000). Compared with the normal group, the pre-pregnancy BMI, proportion of hypertension history, mean arterial pressure (MAP), uterine artery pulsatility index (PI), and serum levels of sFlt-1/PlGF at 20 to 24 weeks and 28-32 weeks were higher in preeclampsia group (P < 0.05). The Cox regression analysis showed that history of hypertension H^R = 2.963 (95% CI: 1.854, 2.939) ], and high pre-pregnancy BMI H^R = 3.662 (95% CI: 2.104, 5.220), MAP H^R = 3.515 (95% CI: 1.523, 5.507), PI H^R = 2.683 (95% CI: 1.359, 4.007), serum sFlt-1/PlGF levels at 20 to 24 weeks H^R = 4.674 (95% CI: 2.379, 6.969), and serum sFlt-1/PlGF levels at 28 to 32 weeks H^R = 3.706 (95% CI: 1.654, 5.758) were risk factors for the occurrence of preeclampsia in women with twin pregnancy (P < 0.05). The equation of the Cox regression for preeclampsia in women with twin pregnancy was PI = 0.412X1 + 0.579X2 + 0.485X3 + 0.418X4 + 0.167X5 + 0.879X6, with an AUC of 0.861 (95% CI: 0.752, 0.970), a sensitivity of 0.922 (95% CI: 0.887, 0.957), a specificity of 0.863 (95% CI: 0.785, 0.941), and a Youden index of 0.785.Conclusions High serum sFlt-1/PlGF levels at 20 to 24 weeks and 28 to 32 weeks are both risk factors for preeclampsia in women with twin pregnancy. Monitoring the serum sFlt-1/PlGF levels in the middle and late pregnancy may contribute to the prediction of the occurrence of preeclampsia.