Adverse pregnancy outcomes and long-term risk of cardiovascular disease in women

怀孕是一种“自然的压力测试”，可能会在早期发现更高的心血管疾病（CVD）风险。 成年期，可能早在临床CVD出现之前。多达三分之一的怀孕是 受不良妊娠结局（APO）影响，定义为先兆子痫，其他高血压疾病， 妊娠糖尿病、胎儿生长受限和/或早产。因此，APO影响超过4000万人， 全球每年有近30%的妇女处于生育年龄。但长期 与APO相关的CVD风险仍然知之甚少，并且没有很好地融入临床实践。一 更好的了解可以促进对年轻妇女的早期干预，并改变她们的长期发展轨迹。 CVD。先前的研究受到载脂蛋白和心血管疾病表型不充分、随访时间和 评估长期风险的统计能力。需要大型队列，对APO进行前瞻性表型分析 妊娠前、妊娠期间和妊娠后的CVD和长期随访。我们假设APO 与更高的长期CVD风险（缺血性心脏病、中风、心力衰竭、心律失常， 外周血管疾病），独立于家族因素。为了验证这个假设， 我们建议对前瞻性表型的APO和长期的APO进行第一次全面评估， CVD风险在一个大型队列中长达48年的随访。我们将分析所有470万人的国家登记数据 1973年至2017年期间，瑞典250万女性的妊娠情况以及所有住院和门诊CVD诊断， 死亡率到2020年。瑞典是一个理想的设置，因为它有足够的个人层面的数据， 人群需要使这项首次的同类研究，心血管疾病的发病率和机制是可比的， 我们我们的目的是（1）确定4种主要的APO（先兆子痫，其他高血压， 疾病，妊娠糖尿病，胎儿生长受限）和整个生命过程中的长期CVD风险;（2） 确定最容易受到APO对长期CVD风险影响的高风险女性亚组;（3） 评估共同的家庭（遗传和/或环境）因素的影响;（4）制定综合的 所有5种主要APO（包括早产）与长期CVD风险相关的模型。拟议 研究意义重大，因为CVD是全球女性死亡的主要原因，而APO是 长期心血管疾病风险的常见和潜在的重要哨兵，但这些风险研究不足， 融入临床实践。它是创新的，因为它将提供第一个全面的评估， 前瞻性表型APO和长期CVD风险，利用相关设计来解开家族性 混杂，并使用250万妇女的无与伦比的数据为所有5个主要APO开发一个综合模型。 这是非常具有成本效益的，因为我们将利用瑞典国家登记处的数据， 或者在美国组装成本过高。研究结果将有助于改善妇女的健康， 与APO相关的长期CVD风险需要指导早期预防和长期临床护理。

Pregnancy is a "natural stress test" that may reveal higher cardiovascular disease (CVD) risks in early adulthood, potentially long before the emergence of clinical CVD. Up to one-third of all pregnancies are affected by an adverse pregnancy outcome (APO), defined as preeclampsia, other hypertensive disorders, gestational diabetes, fetal growth restriction, and/or preterm delivery. Consequently, APOs affect >40 million women worldwide each year and nearly 30% of all women during their reproductive years. However, long-term CVD risks associated with APOs remain poorly understood and not well integrated into clinical practice. A better understanding could facilitate earlier interventions in young women and alter their long-term trajectory of CVD. Prior studies have been limited by insufficient phenotyping of APOs and CVD, follow-up time, and statistical power to assess long-term risks. Large cohorts are needed with prospective phenotyping of APOs and CVD before, during, and after pregnancy, and long-term follow-up. We hypothesize that APOs are associated with higher long-term CVD risks (ischemic heart disease, stroke, heart failure, arrhythmias, peripheral vascular disease) across the life course, independently of familial factors. To test this hypothesis, we propose to conduct the first comprehensive assessment of prospectively phenotyped APOs and long-term CVD risks in a large cohort with up to 48 years of follow-up. We will analyze national registry data for all 4.7 M pregnancies in 2.5 M women in Sweden during 1973-2017 and all inpatient and outpatient CVD diagnoses and mortality through 2020. Sweden is an ideal setting because it has linkable individual-level data for the entire population needed to enable this first-of-its-kind study, and CVD rates and mechanisms are comparable to the US. Our aims are to (1) determine associations between 4 major APOs (preeclampsia, other hypertensive disorders, gestational diabetes, fetal growth restriction) and long-term CVD risks across the life course; (2) identify high-risk subgroups of women who are most susceptible to effects of APOs on long-term CVD risks; (3) assess the influence of shared familial (genetic and/or environmental) factors; and (4) develop an integrated model for association of all 5 major APOs (including preterm delivery) with long-term CVD risks. The proposed research is significant because CVD is the leading cause of death in women worldwide, and APOs are common and potentially important sentinels of long-term CVD risks, yet such risks are understudied and poorly integrated into clinical practice. It is innovative because it will provide the first comprehensive assessment of prospectively phenotyped APOs and long-term CVD risks, utilize co-relative designs to disentangle familial confounding, and develop an integrated model for all 5 major APOs using unparalleled data for 2.5 M women. It is highly cost-efficient because we will leverage data from national registries in Sweden that are unavailable or prohibitively costly to assemble in the US. The results will will help improve women's health by identifying the long-term CVD risks associated with APOs needed to guide early prevention and long-term clinical care.