Adverse Pregnancy Outcomes—Risk Enhancers Whose Time Has Finally Arrived.pdf

Heart disease is the leading cause of death globally for both sexes, affecting 1 in 5 women in the United States.1 Although women have a lower prevalence of obstructive epicardial coronary artery disease compared with men of a similar age, they have higher rates of myocardial ischemia and associated cardiovascular morbidity and mortality.2 While both sex-based differences due to biological factors such as the timing of menarche and menopause and gender-related differences related to social constructs (eg, delays in time to evaluation of chest pain for women vs men) contribute to these disparities, there is a growing recognition that traditional cardiovascular risk calculators fail to account for sex-specific risk factors such as adverse pregnancy outcomes, which are unique to birthing people who predominantly identify as women. Adverse pregnancy outcomes, including pregnancy-induced hypertensive disorders (preeclampsia and gestational hypertension), preterm birth, and fetal growth restriction, are common manifestations of ischemic placental disease3 and share a vascular pathophysiologic origin. Along with gestational diabetes, adverse pregnancy outcomes comprise a group of sex-specific cardiovascular risk enhancers associated with a 2- to 4-fold increased risk of future heart disease.4 Unfortunately, due to a lack of detailed pregnancy history in most existing cohorts and clinical trials of coronary artery disease, to date it has been difficult to examine whether there is a difference in the pathophysiologic development of coronary artery disease in women with a history of adverse pregnancy outcomes compared with those with uncomplicated pregnancies.

心脏病是全球男女死亡的主要原因，影响美国五分之一的女性。 缺血和相关的心血管疾病发病率和死亡率。 2 虽然初潮和绝经时间等生物学因素导致的性别差异以及与社会结构相关的性别差异（例如，女性与男性胸痛评估时间延迟）造成了这些差异，但人们越来越认识到，传统的心血管风险计算器未能考虑到特定性别的风险因素，例如不良妊娠结局，这些因素对于主要被认为是女性的分娩者来说是独一无二的。 不良妊娠结局，包括妊娠高血压疾病（先兆子痫和妊娠高血压）、早产和胎儿生长受限，是缺血性胎盘疾病的常见表现 3 并且具有血管病理生理学起源。 与妊娠糖尿病一起，不良妊娠结局包括一组与未来心脏病风险增加 2 至 4 倍相关的特定性别心血管风险增强因素。 4 不幸的是，由于大多数现有队列缺乏详细的妊娠史和冠状动脉疾病的临床试验，迄今为止，很难检查有不良妊娠结局史的妇女与无并发症妊娠的妇女在冠状动脉疾病的病理生理发展方面是否存在差异。

Coronary computed tomography (CT) angiography is a highly accurate, noninvasive diagnostic test that can be used to assess for presence of obstructive epicardial coronary arterial disease with high sensitivity and negative predictive value.5 While prior strategies of reducing heart disease risk focused on obstructive coronary artery disease burden (defined as stenosis >70%), there is a growing understanding that not only obstructive plaque, but also the presence of any plaque, even noncalcified, is associated with higher risk of cardiovascular morbidity and mortality in a dose-dependent manner (more plaque burden equals greater risk), particularly for women. Similarly, a coronary artery calcium (CAC) score has been shown to be positively correlated with and add incremental value to the assessment of future cardiovascular risk. Compared with a score of 0, even minimal CAC scores are associated with an increased risk of major adverse cardiovascular events.5,6

冠状动脉计算机断层扫描 (CT) 血管造影是一种高度准确、无创的诊断测试，可用于评估是否存在阻塞性心外膜冠状动脉疾病，具有高灵敏度和阴性预测值。 5 虽然先前降低心脏病风险的策略主要集中在阻塞性冠状动脉疾病动脉疾病负担（定义为狭窄 >70%），人们越来越认识到，不仅是阻塞性斑块，而且任何斑块的存在，甚至是非钙化斑块，都以剂量依赖的方式与心血管发病率和死亡率的较高风险相关（更多的斑块负担等于更大的风险），尤其是对女性而言。 同样，冠状动脉钙 (CAC) 评分已被证明与未来心血管风险的评估呈正相关并增加了评估价值。 与 0 分相比，即使是最低的 CAC 分数也与主要不良心血管事件风险增加相关。 5,6

In this issue of JAMA, Sederholm Lawesson and colleagues7 advance knowledge and provide information about the heightened risk of asymptomatic coronary artery disease following individual adverse pregnancy outcomes. Their protocol in the present work from the Swedish Cardiopulmonary Bioimage Study used a single low-dose CT scan to quantify the presence, severity, and extent of atherosclerotic coronary arterial stenoses as well as the presence of noncalcified plaque, and a CAC score. This cross-sectional, population-based cohort study examined 10 528 women with a median age at the time of the scan of 57 years, and in whom imaging was conducted a median of 30 years after their first linked pregnancy in the Swedish National Medical Birth Register. Consistent with other studies, 19% of women had a history of an adverse pregnancy outcome and those individuals also had a higher burden of traditional cardiovascular risk factors, including higher systolic blood pressure and higher prevalence of diabetes, at the time of imaging. The study reported several key findings, including a 3.8% absolute increase in the prevalence of any coronary atherosclerosis in women with a history of adverse pregnancy outcomes compared with those without (32.1% vs 28.3%). The highest increases were seen following a pregnancy affected by preeclampsia (8.0% prevalence increase, 3.1% absolute increase in significant stenosis, 4.2% increase in noncalcified plaque, and 4.1% increase in CAC score >100), with similar findings for gestational hypertension. This translates into an accelerated vascular age, the hypothetical adjustment to chronological age that accounts for the observed severity of coronary artery disease, of 4 to 11 years for women with an exposure to pregnancy-induced hypertensive disorders compared with women without this history, but not for those with history of gestational diabetes or preterm delivery. The findings after delivery of a small-for-gestational-age infant were mixed.

在本期《美国医学会杂志》中，塞德霍尔姆劳森及其同事 7 推进了有关个体不良妊娠结局后无症状冠状动脉疾病风险增加的知识并提供了相关信息。 他们在瑞典心肺生物影像研究的当前工作中使用单次低剂量 CT 扫描来量化动脉粥样硬化性冠状动脉狭窄的存在、严重程度和程度以及非钙化斑块的存在和 CAC 评分。 这项基于人群的横断面队列研究调查了 10 528 名女性，扫描时的中位年龄为 57 岁，在瑞典国家医学分娩中心首次关联怀孕后进行影像学检查的中位时间为 30 年登记。 与其他研究一致，19% 的女性有不良妊娠结局的历史，这些人在影像学检查时也有更高的传统心血管危险因素负担，包括更高的收缩压和更高的糖尿病患病率。 该研究报告了几个关键发现，包括与没有不良妊娠结局史的女性相比，任何冠状动脉粥样硬化的患病率绝对增加 3.8%（32.1% 对 28.3%）。 受先兆子痫影响的妊娠后增幅最大（患病率增加 8.0%，显着狭窄绝对增加 3.1%，非钙化斑块增加 4.2%，CAC 评分 >100 增加 4.1%），妊娠高血压也有类似发现。 这转化为血管年龄加速，即对实际年龄的假设调整，考虑到观察到的冠状动脉疾病的严重程度，与没有这种病史的女性相比，暴露于妊娠诱发的高血压疾病的女性为 4 至 11 岁，但不是对于有妊娠糖尿病或早产史的人。 分娩小于胎龄儿后的结果是混合的。

The authors took their work a step further and examined the burden of CT-diagnosed coronary artery disease in the 83% of women (n = 8334) who had a low predicted 10-year cardiovascular risk (<5%) and would not qualify for aggressive risk factor reduction based on current guidelines. For this Swedish cohort, from a moderate cardiovascular risk region, the SCORE28 algorithm was used to provide a low, moderate, or high risk estimate of fatal and nonfatal incident cardiovascular disease. The SCORE2 risk factors include sex, age, smoking status, systolic blood pressure, and total and high-density lipoprotein cholesterol, but unlike the Pooled Cohort Equations,9 SCORE2 does not consider diabetes, race, or treatment for hypertension, but does incorporate country-specific cardiovascular disease mortality rates by dividing countries in Europe and the Middle East/North Africa into 4 risk regions (low, moderate, high, and very high). For women with a history of preeclampsia who had less than 5% predicted disease risk, their observed burden of significant stenosis (4.5%) was similar to women who had no adverse pregnancy outcome history and intermediate predicted cardiovascular risk (4.8%). Thus, the current risk factor stratification system does an injustice to women with preeclampsia by not accounting for the contribution of preeclampsia as a sex-specific risk factor. This provocative finding confirms what has been shown in 2 prior small studies,10,11 and effectively suggests that women with a history of preeclampsia could benefit from reclassification to a higher level of risk, although the generalizability of this finding to more racially and ethnically diverse or younger populations is unknown.

作者将他们的工作更进一步，检查了 83% 的女性 (n = 8334) 的 CT 诊断的冠状动脉疾病的负担，这些女性的 10 年心血管疾病预测风险较低 (<5%) 并且不符合根据当前指南积极降低风险因素。 对于这个来自中等心血管风险地区的瑞典队列，SCORE28 算法用于提供致命和非致命心血管疾病事件的低、中或高风险估计。 SCORE2 风险因素包括性别、年龄、吸烟状况、收缩压以及总胆固醇和高密度脂蛋白胆固醇，但与汇总队列方程不同的是，9 SCORE2 不考虑糖尿病、种族或高血压治疗，但包含国家/地区 - 通过将欧洲和中东/北非国家划分为 4 个风险区域（低、中、高和极高）的特定心血管疾病死亡率。 对于有先兆子痫病史且预测疾病风险低于 5% 的女性，她们观察到的显着狭窄负担 (4.5%) 与没有不良妊娠结局史和中度预测心血管风险 (4.8%) 的女性相似。 因此，当前的风险因素分层系统没有将先兆子痫作为性别特异性风险因素的贡献考虑在内，从而对患有先兆子痫的女性造成了不公平。 这一激动人心的发现证实了之前 2 项小型研究的结果，10,11 并有效地表明，有先兆子痫病史的女性可以从重新分类到更高的风险水平中获益，尽管这一发现对更多种族和族裔的普遍性或更年轻的人群是未知的。

Prior attempts at incorporating adverse pregnancy outcomes into cardiovascular disease risk calculators have failed to provide a meaningful shift in disease classification status.12,13 This may in part be due to the grouping of adverse pregnancy outcomes together as an exposure to enhance power; it is likely that some adverse pregnancy outcomes mediate risk through their association with a heightened burden of traditional risk factors postpregnancy, while other adverse pregnancy outcomes like preeclampsia exert a direct effect on the coronary vessels, among other targets. Clustering vascular and nonvascular adverse pregnancy outcomes together may bias the reclassification schema toward the null, resulting in a smaller effect after accounting for traditional risk factors. Thus, before moving forward to attempt to refine the currently available risk calculators to include all adverse pregnancy outcomes, clinicians must first better understand individual adverse pregnancy outcomes and whether they enhance risk directly or through a shared burden of traditional risk factors. Despite the relatively homogeneous nature of this Scandinavian cohort, one of its great strengths is the population-based study design. Most prior studies examining cardiovascular disease during and after adverse pregnancy outcomes have been retrospective, single-center, cross-sectional analyses examining referred populations of limited size and often lacking adequate control groups. Given the overlap in risk factors for adverse pregnancy outcomes and cardiovascular disease, these studies have not been able to clarify contributing roles of specific adverse pregnancy outcomes in the development of heart disease. The current work is an important step in that direction, demonstrating the independent risk of coronary disease following a hypertensive disorder of pregnancy, while confirming that most of the risk experienced by individuals with a history of other adverse pregnancy outcomes such as gestational diabetes is mediated predominantly by conventional risk factors.

先前将不良妊娠结局纳入心血管疾病风险计算器的尝试未能对疾病分类状态提供有意义的转变。12,13 这可能部分是由于将不良妊娠结局归为一组以增强功效； 某些不良妊娠结局可能会通过与妊娠后传统风险因素负担加重相关来调节风险，而先兆子痫等其他不良妊娠结局则对冠状血管等目标产生直接影响。 将血管性和非血管性不良妊娠结局聚集在一起可能会使重新分类方案偏向于零，导致在考虑传统风险因素后影响较小。 因此，在继续尝试改进当前可用的风险计算器以包括所有不良妊娠结局之前，临床医生必须首先更好地了解个体不良妊娠结局，以及它们是直接增加风险还是通过传统风险因素的共同负担来增加风险。 尽管这个斯堪的纳维亚队列具有相对同质性，但其最大优势之一是基于人群的研究设计。 大多数先前检查不良妊娠结局期间和之后心血管疾病的研究都是回顾性的、单中心的、横断面分析，检查的是规模有限且通常缺乏足够对照组的转诊人群。 鉴于不良妊娠结局和心血管疾病的危险因素存在重叠，这些研究未能阐明特定不良妊娠结局在心脏病发展中的作用。 目前的工作是朝着这个方向迈出的重要一步，证明了妊娠期高血压疾病后冠心病的独立风险，同时证实有妊娠糖尿病等其他不良妊娠结局史的个体所经历的大部分风险主要是介导的由传统的风险因素。

Failure to recognize, prevent, and treat the unique aspects of heart disease in women has resulted in less aggressive lifestyle and medical interventions in women relative to men, leading to potentially avoidable morbidity and mortality.14 To close the gap between currently delivered and ideal care, and to improve the cardiovascular health of women, clinicians must better understand the unique aspects and mechanistic pathways of heart disease in women. The study by Sederholm Lawesson and colleagues takes us one step closer to parity. While further data accumulate to refine risk calculators and prospectively test whether the addition of adverse pregnancy outcomes to cardiovascular risk stratification is warranted, there are steps that can be taken now to do better by our female patients. Taking a pregnancy history when assessing cardiovascular risk and incorporating adverse pregnancy outcomes, particularly preeclampsia and gestational hypertension, into the risk/benefit discussion around primary preventive strategies and risk factor targets is imperative. Clinicians must also educate birthing people at the time of their pregnancy to understand the impact of an adverse pregnancy outcome on their risk of future heart disease, encourage them to receive timely preventive care focused on risk factor modification, and empower them to share this important medical history with future clinicians if they are not asked about it. There is no time like the present to redouble the efforts to reduce cardiovascular disease in women.

未能识别、预防和治疗女性心脏病的独特方面，导致女性的生活方式和医疗干预相对于男性而言较不积极，从而导致可能避免的发病率和死亡率。 14 缩小目前提供的护理与理想护理之间的差距，为了改善女性的心血管健康，临床医生必须更好地了解女性心脏病的独特方面和机制途径。塞德霍尔姆劳森及其同事的研究使我们更接近均等。 虽然进一步的数据积累可以改进风险计算器并前瞻性地测试是否有必要将不良妊娠结果添加到心血管风险分层中，但现在可以采取一些措施让我们的女性患者做得更好。 在评估心血管风险并将不良妊娠结局（尤其是先兆子痫和妊娠高血压）纳入围绕主要预防策略和风险因素目标的风险/收益讨论时，必须了解妊娠史。 临床医生还必须在怀孕期间对分娩的人进行教育，让他们了解不良妊娠结局对他们未来患心脏病风险的影响，鼓励他们及时接受以风险因素改变为重点的预防性护理，并使他们能够分享这一重要的医学知识与未来的临床医生的历史，如果他们没有被问到的话。 现在是加倍努力减少女性心血管疾病的最佳时机。