妊娠期高血压疾病评估中孕早期PAPP-A、PLGF、Fibulin-3、Ang-2、Hcy的应用价值及其与病情程度的关系

Application values of PAPP-A, PLGF, Fibulin-3, Ang-2 and Hcy in early pregnancy in assessment of hypertensive disorders complicating pregnancy and their relationships with severity of the disease

摘要

目的 探讨妊娠期高血压疾病评估中孕早期妊娠相关血浆蛋白A(PAPP-A)、胎盘生长因子(PLGF)、细胞外基质蛋白-3(Fibulin-3)、血管生成素2(Ang-2)、同型半胱氨酸(Hcy)的应用价值及其与病情程度的关系。方法 采用巢式病例对照设计,纳入2022年1月至2024年3月在我院建档并进行孕早期筛查的单胎妊娠孕妇371例。根据随访至妊娠结束的结局,将发生妊娠期高血压疾病者作为A组186例(排除1例失访最终纳入185例),并进一步分为Ⅰ组(妊娠期高血压)98例、Ⅱ组(轻度子痫前期)58例、Ⅲ组(重度子痫前期)29例;将全程血压正常、无妊娠期并发症者185名纳入B组作为对照组。比较各组临床资料、孕早期血清PAPP-A、PLGF、Fibulin-3、Ang-2、Hcy水平,将具有显著差异的单因素分析变量用作自变量纳入多因素Logistic回归分析。应用相关性分析各检测指标与妊娠期高血压疾病严重程度的关系。采用受试者工作特征(ROC)曲线分析预测价值。结果 A组孕早期血清PAPP-A、PLGF、Ang-2、Fibulin-3水平均低于B组,血清Hcy水平则高于B组(t=76.764、46.205、34.508、26.412、62.255,P<0.05)。Ⅲ组孕早期血清PAPP-A、PLGF、Fibulin-3、Ang-2水平低于Ⅱ组,Ⅱ组低于Ⅰ组;Ⅲ组孕早期血清Hcy水平则高于Ⅱ组,Ⅱ组高于Ⅰ组(F=39.112、66.799、125.093、160.015、91.540,P<0.05)。Ⅲ组、Ⅱ组、Ⅰ组及B组四组间不良妊娠结局总发生率差异有统计学意义(χ²=40.106,P<0.001)。血清Hcy水平与妊娠期高血压疾病严重程度呈正相关(r=0.735,P<0.05),血清PAPP-A、PLGF、Fibulin-3、Ang-2水平则与妊娠期高血压疾病严重程度呈负相关(r=-0.713、-0.782、-0.621、-0.744,P<0.05)。多因素Logistic回归分析结果显示,血清Hcy水平升高(OR=1.399,95%CI:1.146~1.709)为妊娠期高血压疾病发生的影响因素,血清PAPP-A(OR=0.427,95%CI:0.221~0.824)、PLGF(OR=0.536,95%CI:0.330~0.869)、Fibulin-3(OR=0.487,95%CI:0.277~0.857)、Ang-2水平(OR=0.605,95%CI:0.422~0.868)升高均为妊娠期高血压疾病发生的保护因素(P<0.05)。ROC曲线分析显示,孕早期血清PAPP-A、PLGF、Fibulin-3、Ang-2、Hcy联合检查的曲线下面积(AUC)最高(AUC=0.880,95%CI:0.842~0.911,P<0.05),灵敏度和特异度分别为88.65%、78.38%。结论 孕早期血清PAPP-A、PLGF、Fibulin-3、Ang-2、Hcy水平与妊娠期高血压疾病的发生及病情严重程度密切相关,且五者联合检测可显著提升疾病的早期预测效能,有助于识别高风险人群,改善母婴预后。

Abstract

Objective To analyze application values of pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PLGF), extracellular matrix protein-3 (also called Fibulin-3), angiopoietin-2 (Ang-2), homocysteine (Hcy) in the first trimester of pregnancy in assessment of hypertensive disorders complicating pregnancy (HDCP) and their relationships with severity of the disease. Methods In nested case-control study design, 371 singleton pregnant women who received regular prenatal examination and early pregnancy screening in the first trimester of pregnancy in our hospital from January 2022 to March 2024 were selected. According to pregnancy outcome and follow-up result, 186 pregnant women with HDCP (185 pregnant women ultimately included) were assigned to Group A, and they were further divided into gestational hypertension group (group Ⅰ, n=98), mild preeclampsia group (group Ⅱ, n=58) and severe preeclampsia group (group Ⅲ, n=29). Other 185 pregnant women with normal blood pressure during whole pregnancy and without pregnancy-related complications were included in Group B (control group). Clinical data, serum levels of PAPP-A, PLGF, Fibulin-3, Ang-2 and Hcy in early pregnancy of the pregnant women were compared between the Group A and the Group B. The variables with significant differences in univariate analysis were incorporated as independent variables into multivariate Logistic regression analysis. Spearman correlation analysis was applied to analyze relationships between these indexes and severity of HDCP. Receiver operating characteristic (ROC) curve was used to analyze predictive values of PAPP-A, PLGF, Fibulin-3, Ang-2 and Hcy in early pregnancy for severity of HDCP. Results The serum levels of PAPP-A, PLGF, Ang-2 and Fibulin-3 in early pregnancy of the pregnant women in the Group A were significantly lower than those in the Group B, while serum Hcy level was higher than that in the Group B (t=76.764, 46.205, 34.508, 26.412 and 62.255 respectively, all P<0.05). In the Group A, the serum levels of PAPP-A, PLGF, Fibulin-3 and Ang-2 in early pregnancy of the pregnant women in the group Ⅲ were lower than those in the group Ⅱ, and those in the group Ⅱ were lower than those in the group Ⅰ in turn; while, the serum Hcy level of the pregnant women in the group Ⅲ was higher than that in the group Ⅱ, and that in the group Ⅱ was higher than that in the group Ⅰ in turn (F=39.112, 66.799, 125.093, 160.015 and 91.540 respectively, all P<0.05). There was a statistically significant difference in overall incidence of adverse pregnancy outcomes among the group Ⅲ, the group Ⅱ, the group Ⅰ and the Group B (χ ²=40.106, P<0.001). The serum Hcy level was positively correlated with severity of HDCP (r=0.735, P<0.05), whereas the serum levels of PAPP-A, PLGF, Fibulin-3 and Ang-2 were negatively correlated with severity of HDCP (r=-0.713, -0.782, -0.621 and -0.744 respectively, all P<0.05). Multivariable Logistic regression analysis showed that elevated serum Hcy level (OR=1.399, 95% CI: 1.146-1.709) was a risk factor for HDCP, while elevated serum levels of PAPP-A (OR=0.427, 95% CI: 0.221-0.824), PLGF (OR=0.536, 95% CI: 0.330-0.869), Fibulin-3 (OR=0.487, 95% CI: 0.277-0.857), and Ang-2 (OR=0.605, 95% CI: 0.422-0.868) were the protective factors (all P<0.05). ROC curve analysis showed that combination of serum PAPP-A, PLGF, Fibulin-3, Ang-2 and Hcy in early pregnancy yielded the highest area under the curve (AUC) (AUC=0.880, 95% CI: 0.842-0.911, P<0.05), with a sensitivity of 88.65% and a specificity of 78.38% respectively. Conclusion The serum levels of PAPP-A, PLGF, Fibulin-3, Ang-2 and Hcy in early pregnancy are closely related to occurrence and severity of HDCP. The combined detection of these five indexes could significantly improve early prediction efficiency for the disease, help identify those HDCP high-risk populations, and improve maternal and neonatal outcomes.

关键词

妊娠期高血压疾病 / 孕早期 / 病情程度 / 妊娠相关血浆蛋白A / 胎盘生长因子 / 细胞外基质蛋白-3 / 血管生成素2 / 同型半胱氨酸

Key words

hypertensive disorders complicating pregnancy / early pregnancy / severity of disease / pregnancy-associated plasma protein A / placental growth factor / extracellular matrix protein-3 / angiopoietin 2 / homocysteine

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基金资助

河北省2021年度医学科学研究课题计划(20211762)