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

怀孕是一种“自然压力测试”，可以在怀孕早期发现较高的心血管疾病(CVD)风险。 成年期，可能在临床脑血管病出现之前很久。高达三分之一的怀孕是 受到不良妊娠结局(APO)的影响，定义为先兆子痫、其他高血压疾病、 妊娠期糖尿病、胎儿生长受限和/或早产。因此，APO影响了4000万人 全世界每年都有妇女，占所有生育期妇女的近30%。然而，从长远来看， 与APOS相关的心血管风险仍然知之甚少，也没有很好地融入临床实践。一个 更好的理解可以促进对年轻女性的早期干预，并改变她们的长期轨迹 心血管疾病。以前的研究受到载脂蛋白和心血管疾病表型、随访时间和 评估长期风险的统计能力。APO的预期表型需要大量的队列研究 并对孕前、孕中、孕后心血管疾病进行长期随访。我们假设APO是 与较高的长期心血管疾病风险(缺血性心脏病、中风、心力衰竭、心律失常、 外周血管疾病)贯穿整个生命过程，不受家族因素的影响。为了检验这一假设， 我们建议对预期的APO表型和长期APO进行第一次全面评估 心血管疾病风险在长达48年的随访的大型队列中。我们将分析所有470万人的国家注册数据 1973-2017年间瑞典250万妇女的怀孕情况以及所有住院和门诊心血管疾病诊断和 到2020年的死亡率。瑞典是一个理想的环境，因为它拥有可链接的整个 实现这项首个此类研究所需的人群，以及心血管疾病发生率和机制可与 我们。我们的目标是(1)确定4个主要APO(先兆子痫、其他高血压)之间的关联 疾病、妊娠期糖尿病、胎儿生长受限)和生命过程中的长期心血管疾病风险； 确定最容易受到APO对长期心血管疾病风险影响的高危妇女亚群；(3) 评估共同的家庭(遗传和/或环境)因素的影响；和(4)制定综合的 所有5个主要APO(包括早产)与长期心血管疾病风险的关联模型。建议数 研究意义重大，因为心血管疾病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重要指标，但这种风险研究不足，而且研究不足。 与临床实践相结合。它具有创新性，因为它将提供第一个全面的评估 前瞻性表型APO和长期心血管疾病风险，利用相关设计来分离家族性 令人困惑，并使用250万妇女的无与伦比的数据为所有5个主要的APO开发了一个综合模型。 它具有很高的成本效益，因为我们将利用瑞典国家登记处无法获得的数据 或者在美国组装成本高得令人望而却步。这一结果将有助于改善妇女的健康状况，因为 与APO相关的长期心血管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.