Preterm birth and long-term risk of cardiovascular disease in mothers and offspring

目前，美国每10个新生儿中约有1个早产（胎龄<37周）， 由于治疗的进步，>95%的早产儿存活至成年。最近的研究表明 早产儿的母亲和后代患代谢综合征的长期风险更高， 心血管疾病（CVD）的主要危险因素。早产的母亲也可能有更高的长期- 长期CVD发病率;然而，PTB成年后代CVD风险的报道一直存在争议。一 最近的一个跨NIH工作组强调迫切需要进行以下研究：（1）对长期CVD风险进行分层 通过PTB亚型（例如，自发性vs.由于母体/胎儿状况导致的适应症），以帮助阐明潜在的 机制和定制长期的病人护理;（2）允许更长的随访到成年中期或以后， 疾病风险仍然知之甚少;（3）包括大样本量，以允许检查长期 具有高统计功效的结果。我们假设：（1）PTB与更高的长期风险相关 CVD（即，缺血性心脏病、脑血管疾病、心力衰竭、外周血管疾病、主动脉 在母亲和成年后代中，剂量-反应关系在妊娠早期增加 年龄;和（2）这些相关性存在于所有主要类型的PTB中，但对于与胎盘相关的PTB来说更强 不足（例如，先兆子痫或糖尿病），其与氧化应激和炎症有关， 导致结构性微血管变化。为了解决这些假设，我们建议进行第一次 母亲及其成年人中PTB及其亚型与CVD风险的关系 后代我们将收集和分析国家数据库，其中包含约230万至约120万的出生人数。 1973-1995年期间瑞典的母亲以及2015年之前所有CVD住院和门诊诊断。我们 具体目标是：（1）检查PTB及其亚型与CVD和CVD相关的长期风险的关系。 结果（高血压，糖尿病，睡眠呼吸暂停）在母亲和成年后代;（2）确定是否有 更容易受到PTB长期风险影响的社会人口统计学亚组;（3）探索 未测量的家族（遗传和共同环境）因素对PTB-CVD的潜在混杂影响 使用相关分析的关联。拟议的研究是有意义的，因为PTB是常见的， 前所未有的幸存者数量正在进入成年期（在美国约为40万/年）;因此， 长期风险的适度增加会转化为巨大的人口健康负担。它是创新的，因为它 将首次全面检查PTB及其亚型与CVD风险的关系，并使用 共相关设计以解开家族混杂。这是非常具有成本效益的，因为我们将组装 这些数据来自国家登记处，在美国无法获得或收集成本过高。结果 通过建立与PTB及其亚型相关的长期CVD风险， 母亲和成年后代，并为更好的风险评估和长期护理提供临床指南。

Currently about 1 of every 10 births in the US occurs preterm (gestational age <37 completed weeks), and because of advances in treatment, >95% of preterm infants survive to adulthood. Recent research has shown that both the mothers and offspring of preterm birth (PTB) have higher long-term risks of metabolic syndrome, a major risk factor for cardiovascular disease (CVD). Mothers who deliver preterm may also have higher long- term CVD incidence; however, the reported risks of CVD in adult offspring of PTB have been conflicting. A recent Trans-NIH Working Group highlighted a pressing need for studies that: (1) stratify long-term CVD risks by PTB subtype (e.g., spontaneous vs. indicated due to maternal/fetal conditions) to help elucidate underlying mechanisms and tailor long-term patient care; (2) allow longer follow-up into mid-adulthood or later when disease risks remain poorly understood; and (3) include large sample sizes to allow examination of long-term outcomes with high statistical power. We hypothesize that: (1) PTB is associated with higher long-term risks of CVD (i.e., ischemic heart disease, cerebrovascular disease, heart failure, peripheral vascular disease, aortic disease) among mothers and adult offspring, with increasing dose-response relationships by earlier gestational age; and (2) These associations exist for all major types of PTB, but are stronger for those related to placental insufficiency (e.g., preeclampsia or diabetes), which is associated with oxidative stress and inflammation, leading to structural microvascular changes. To address these hypotheses, we propose to conduct the first comprehensive examination of PTB and its subtypes in relation to CVD risks among mothers and their adult offspring. We will assemble and analyze national databases containing all ~2.3 million births to ~1.2 million mothers in Sweden during 1973-1995 and all inpatient and outpatient diagnoses of CVD through 2015. Our specific aims are to: (1) Examine PTB and its subtypes in relation to long-term risks of CVD and CVD-related outcomes (hypertension, diabetes, sleep apnea) in mothers and adult offspring; (2) determine if there are sociodemographic subgroups that are more susceptible to PTB effects on long-term risks; and (3) explore potential confounding effects of unmeasured familial (genetic and shared environmental) factors on PTB-CVD associations using co-relative analyses. The proposed research is significant because PTB is common and unprecedented numbers of survivors are now reaching adulthood (~400,000/year in the US); thus even modestly increased long-term risks translate into a large population health burden. It is innovative because it will provide the first comprehensive examination of PTB and its subtypes in relation to CVD risks, and use a co-relative design to disentangle familial confounding. It is highly cost-efficient because we will assemble these data from national registries that are unavailable or prohibitively costly to collect in the US. The results will have major impacts by establishing the long-term CVD risks associated with PTB and its subtypes among mothers and adult offspring, and informing clinical guidelines for better risk assessment and long-term care.