大气PM2.5暴露与孕妇子痫前期发病的关系及内皮功能损伤在其中的作用研究

Preeclampsia is a pregnancy-induced hypertensive disorder characterized by high blood pressure and proteinuria after the 20th week of pregnancy. It is one of the leading causes of maternal mortality and morbidity worldwide and is associated with adverse pregnancy outcomes including perinatal death, preterm birth, and intrauterine growth retardation. The cause of preeclampsia remains unclear now. Studies from developed countries with low-level air pollution have shown that inhaling ambient fine particulate matter (aerodynamic diameter ≤ 2.5μm, PM2.5) among pregnant women was associated with preeclampsia. They observed elevated preeclampsia morbidity with increasing ambient PM2.5 mass concentration. However, little studies from the countries with serious air pollution have detected the exposure- response relationship. Evidence from experimental studies suggests that endothelial dysfunction may play an important role in preeclampsia development after ambient PM2.5 exposure. However, no epidemiological study has detected endothelial dysfunction of pregnant women to test this hypothesis..In China, ambient PM2.5 mass concentration is far higher than that in developed countries, and Pearl River Delta region is an area characterized by high secondary pollutants' concentration. To explore the effects of ambient PM2.5 exposure on preeclampsia among Chinese pregnant women, we will design a prospective cohort study. This study will be conducted in Heshan city, which located in Pearl River Delta region. We plan to enroll about 1600 pregnant women and follow up for the whole pregnancy for each woman. The average daily ambient PM2.5 mass concentration will be calculated for each subject among several periods: 3 months before conception, the first trimester, the second trimester, the third trimester and the entire pregnancy. Logistic regression will be used to estimate the effects of ambient PM2.5 concentration of each period on preeclampsia. The results will be an important addition for the exposure-response relationship of ambient PM2.5 and preeclampsia in high PM2.5 level. Moreover, we will detect indicators of endothelial dysfunction, including circulating sFlt-1, sEng, PIGF, VEGF levels and flow mediated dilation within each period, and then apply structural equation model to build "ambient PM2.5 exposure-endothelial dysfunction-preeclampsia" path, to confirm the role of endothelial dysfunction in the relationship of PM2.5 exposure and preeclampsia. The results of our study can provide reference for pregnant women to protect them from PM2.5 exposure during critical windows, and in turn prevent preeclampsia and preeclampsia related adverse pregnancy outcomes.

子痫前期严重威胁母婴健康，是围产医学研究的难点和热点。低污染国家的人群研究提示，大气PM2.5暴露可增加子痫前期的发病风险。但PM2.5高浓度暴露对子痫前期的影响程度和不同孕期暴露的健康效应差异，尚不清楚。我国大气污染严重，但缺乏相关研究。为此，本研究拟基于“孕妇于某一时期（孕前、孕早、中、晚期）暴露于PM2.5-血管内皮功能损伤-子痫前期发生”的暴露反应关系假设，开展前瞻性研究。以PM2.5污染严重，污染特征明显的珠三角地区为研究现场，依托课题组现建立的孕妇队列，通过随访分析不同孕期暴露对子痫前期发病的影响并建立“大气PM2.5暴露-内皮功能损伤-子痫前期”因果通径，从而验证研究假设，以评估各孕期PM2.5暴露影响子痫前期发病的效应。研究结果可为高浓度下PM2.5暴露与子痫前期的暴露反应关系补充研究证据，也可为确定暴露敏感孕期提供依据，指导孕期防护，预防子痫前期及其导致的不良妊娠结局发生

本项目原计划建立1600例对象的前瞻性孕妇队列并随访，分析孕前及不同孕期大气PM2.5 暴露与子痫前期发病的暴露反应关系，评估我国大气PM2.5暴露影响子痫前期发病的效应，并探讨孕妇暴露的敏感时期。本项目各年度均按照计划执行，于2017年5月开始，依托广州市番禺区何贤纪念医院建立孕妇队列。截止2019年11月，已建立了包含5095人的孕妇队列，问卷收集了研究对象的相关信息，并采用反距离加权法完成了所有研究对象从怀孕至分娩期间的PM2.5暴露评估。同时，收集了研究对象各孕期血样3651份。由于经费限制，无法对所有血样进行检测，本研究进而在队列的基础上设计了巢式病例对照研究。首先按照孕妇年龄±2岁进行子痫前期和对照1：1匹配，得到206例病例和210例对照，对研究对象的661份血样进行检测，检测指标包括sFlt-1、sEng和PlGF。..在建立队列的同时，为了保证成果产出，项目组获取了深圳市（2003-2012年）和广州市（2015-2017年）的出生登记数据，开展了相关的研究，目前已发表SCI论文8篇，其中7篇影响因子>5.0。我们发现孕早期、孕中期暴露于PM10和SO2均可增加子痫前期的发病风险。技术方面，建立了孕期空气暴露影响不良孕产结局的关键窗口期的研究方法，发现18-31孕周是空气污染（PM2.5、PM10、NO2、O3）暴露增加早产风险的关键窗口期，而4-10周是SO2暴露增加妊娠期糖尿病发病风险的关键时期。此外，本项目通过文献综述，发现环境温度是影响成年人血压的重要因素，进而从大气环境整体暴露的视角出发，探讨不良气象条件与空气污染的交互作用对不良出生结局的影响，发现怀孕季节、怀孕期间的温度等与空气污染产生交互作用影响子痫前期、早产、低出生体重的发生风险。 ..下一步，本研究将基于队列已经收集的数据，进一步分析数据以补充研究成果。分析计划包括：1）采用Logistic回归，估计每一个孕妇孕前3个月，孕早、中、晚期和整个孕期大气PM2.5暴露对子痫前期发病的影响。2）利用结构方程模型，建立“大气PM2.5暴露-内皮功能损伤（血清sFlt-1、sEng和PlGF）-子痫前期”路径。