Triggers of Abruptio Placentae - A Case Crossover Study of an Ischemic Placental

胎盘早剥的触发因素——缺血性胎盘的病例交叉研究

基本信息

批准号：
8701313
负责人：
Cande V. Ananth
金额：
$ 52.17万
依托单位：
SWEDISH MEDICAL CENTER, FIRST HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-10 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8701313
关键词：
Abdomen Abruptio Placentae Acute Address Alcohol consumption Blood Platelets Cells Chronic Clinical Coagulation Process Collection Complication Cross-Over Studies Crossover Design DNA Data Databases Development Diagnosis Discipline of obstetrics Disease Enrollment Epidemiologic Studies Epidemiology Etiology Evaluation Exertion Exposure to Fetal Death Fetal Growth Retardation Fibrinolysis Functional disorder Genes Genetic Goals Haplotypes Hemorrhagic Shock Hour Hypoxia Implant Infant Infarction Infection Inflammation Inherited Intervention Interview Ischemia Kidney Failure Life Medical Records Methods Mothers Muscle Cramp Newborn Infant Pathogenesis Pathway interactions Perinatal Disorder Persons Peru Physical activity Placenta Placental Infarction Pre-Eclampsia Pregnancy Pregnancy Outcome Premature Birth Prevention Prevention strategy Preventive Intervention Primary Prevention Public Health Relative Risks Renin-Angiotensin System Research Research Design Research Personnel Risk Risk Factors Saliva Sampling Scanning Secondary to Sex Behavior Single Nucleotide Polymorphism Specific qualifier value Specimen Staging Sympathetic Nervous System Trauma Uterine hemorrhage Vagina Variant Vehicle crash Woman advanced maternal age adverse outcome angiogenesis base binge drinking case control clinical care density design falls fetal folic acid metabolism genetic variant hazard insight intimate partner violence maternal cigarette smoking novel strategies premature public health relevance screening

项目摘要

DESCRIPTION (provided by applicant): Abruptio placentae (AP), the premature separation of the placenta, is a life threatening obstetric condition that complicates roughly 1-2 percent of all pregnancies. Pathophysiologic mechanisms involved in AP (and related perinatal disorders - preterm birth, preeclampsia, and intrauterine growth restriction) include uteroplacental ischemia, underperfusion, chronic hypoxia, and infarctions. On this basis, investigators have begun to conceptualize abruption as an "ischemic placental disorder" characterized by acute and chronic pathophysiological features. Furthermore, evidence suggests that transient activation of the sympathetic nervous system might trigger AP. The etiology of AP remains unknown, though results from previous studies suggest some risk factors and emerging evidence suggest a significant genetic component in the pathogenesis of AP. At present, neither an accurate prediction nor prevention of AP is possible. We seek to increase our understanding of the epidemiology and pathophysiology of AP by conducting a large multi-center epidemiologic study of AP in Lima, Peru. We will use the self-matched case-crossover design to evaluate the acute effects of: 1) maternal smoking and alcohol consumption; 2) physical exertion; 3) sexual activity; 4) abdominal trauma secondary to falls or motor vehicle crashes; and 5) exposure to intimate partner violence as potential "triggers" of AP. The risk of AP will be assessed during pre-specified hazard periods. We will also use the case-control replicative (two stage) study design to study genetic variants that influence the pathogenesis of AP in well characterized 900 mother-infant abruption case pairs and 900 mother-infant control pairs. We plan to focus on specific gene pathways, including coagulation, fibrinolysis, platelet function, infection and inflammation, angiogenesis, folate metabolism, and the renin-angiotensin systems that have previously been associated with AP. In Stage 1, we will use a high-density single nucleotide polymorphism (SNP) "1536-chip" on the 1st half of samples to scan maternal and infant SNPs and SNP haplotypes for association with AP. In Stage 2, we will select ~200 of the most pertinent candidate SNPs for replication in the 2nd half of samples. We hypothesize that genes associated with substantial relative risk of AP in Stage 1 will replicate in the independent sample set used in Stage 2. Results from these proposed studies will reveal new insights into the pathophysiology of AP by formally exploring possible interactions between prolonged and habitual exposures (e.g., habitual alcohol consumption and physical activity) and triggering effects of factors such as binge drinking or extreme physical exertion. Results will also yield new insights into the inherited genetic bases of AP. Collectively, these new insights may facilitate the development of new approaches for the primary prevention of AP (at the public health level) and may also facilitate the development of new therapies and methods for diagnosis. PUBLIC HEALTH RELEVANCE: Abruptio placentae (AP), is of global public health importance in large part because of its association with adverse outcomes in newborns and mothers including preterm delivery, fetal death, maternal hemorrhagic shock, and renal failure. We will use the self-matched case-crossover design to study the transient effects of putative "triggers" of AP; and we will use the case-control design to study genetic variants that influence the pathogenesis of AP in 900 mother-infant abruption case pairs and 900 mother-infant control pairs. Results from our research have a very high potential for yielding etiologic and clinical information that may prove to be effective in the identification of women at greatest need of specific preventive interventions and specialized clinical care.

描述（由申请人提供）：胎盘早剥 (AP)，即胎盘过早分离，是一种危及生命的产科疾病，约占所有妊娠的 1-2%。 AP（以及相关围产期疾病 - 早产、先兆子痫和宫内生长受限）涉及的病理生理机制包括子宫胎盘缺血、灌注不足、慢性缺氧和梗塞。在此基础上，研究人员开始将胎盘早剥概念化为一种以急性和慢性病理生理学特征为特征的“缺血性胎盘疾病”。此外，有证据表明交感神经系统的短暂激活可能会引发 AP。 AP 的病因仍不清楚，但之前的研究结果表明了一些危险因素，并且新出现的证据表明 AP 发病机制中存在重要的遗传因素。目前，AP的准确预测和预防都是不可能的。我们在秘鲁利马进行了一项大型多中心 AP 流行病学研究，旨在加深对 AP 流行病学和病理生理学的了解。我们将使用自我匹配病例交叉设计来评估以下因素的急性影响：1）母亲吸烟和饮酒； 2）体力消耗； 3）性活动； 4）跌倒或机动车碰撞继发的腹部外伤； 5) 接触亲密伴侣暴力是 AP 的潜在“触发因素”。 AP 风险将在预先指定的危险期内进行评估。我们还将使用病例对照复制（两阶段）研究设计，在 900 个母婴早剥病例对和 900 个母婴对照对中研究影响 AP 发病机制的遗传变异。我们计划重点关注特定的基因途径，包括凝血、纤溶、血小板功能、感染和炎症、血管生成、叶酸代谢以及先前与 AP 相关的肾素-血管紧张素系统。在第一阶段，我们将在第一半样本上使用高密度单核苷酸多态性（SNP）“1536芯片”来扫描母婴SNP和SNP单倍型以查找与AP的关联。在第 2 阶段，我们将选择约 200 个最相关的候选 SNP 在后半部分样本中进行复制。我们假设与第一阶段 AP 显着相对风险相关的基因将在第二阶段使用的独立样本集中复制。这些拟议研究的结果将通过正式探索长期暴露和习惯性暴露之间可能的相互作用，揭示对 AP 病理生理学的新见解（例如，习惯性饮酒和体力活动）以及酗酒或过度体力消耗等因素的触发效应。研究结果还将对 AP 的遗传基础产生新的见解。总的来说，这些新见解可能会促进 AP 一级预防（公共卫生层面）新方法的开发，也可能会促进新疗法和诊断方法的开发。公共卫生相关性：胎盘早剥 (AP) 具有全球公共卫生重要性，很大程度上是因为它与新生儿和母亲的不良后果相关，包括早产、胎儿死亡、产妇失血性休克和肾衰竭。我们将使用自匹配案例交叉设计来研究假定的AP“触发器”的瞬态效应；我们将采用病例对照设计，在900对母婴早剥病例和900对母婴对照中研究影响AP发病机制的遗传变异。我们的研究结果非常有可能产生病因学和临床信息，这些信息可能被证明可以有效地识别最需要特定预防干预措施和专门临床护理的女性。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Maternal blood mitochondrial DNA copy number and placental abruption risk: results from a preliminary study.

母血线粒体 DNA 拷贝数和胎盘早剥风险：初步研究结果。

DOI：
发表时间：
2013
期刊：
影响因子：
0
作者：
Williams, Michelle A;Sanchez, Sixto E;Ananth, Cande V;Hevner, Karin;Qiu, Chunfang;Enquobahrie, Daniel A
通讯作者：
Enquobahrie, Daniel A

Abruptio placentae risk and genetic variations in mitochondrial biogenesis and oxidative phosphorylation: replication of a candidate gene association study.

胎盘早剥风险和线粒体生物发生和氧化磷酸化的遗传变异：候选基因关联研究的复制。

DOI：
发表时间：
2018
期刊：
影响因子：
9.8
作者：
Workalemahu, Tsegaselassie;Enquobahrie, Daniel A;Gelaye, Bizu;Thornton, Timothy A;Tekola;Sanchez, Sixto E;Garcia, Pedro J;Palomino, Henry G;Hajat, Anjum;Romero, Roberto;Ananth, Cande V;Williams, Michelle A
通讯作者：
Williams, Michelle A

Maternal Early Pregnancy Serum Metabolomics Profile and Abnormal Vaginal Bleeding as Predictors of Placental Abruption: A Prospective Study.

孕早期孕妇血清代谢组学特征和异常阴道出血作为胎盘早剥的预测因子：一项前瞻性研究。

DOI：
发表时间：
2016
期刊：
影响因子：
3.7
作者：
Gelaye B;Sumner SJ;McRitchie S;Carlson JE;Ananth CV;Enquobahrie DA;Qiu C;Sorensen TK;Williams MA
通讯作者：
Williams MA

Absence of circadian rhythms of preterm premature rupture of membranes and preterm placental abruption.

早产胎膜早破和早产胎盘早剥的昼夜节律缺失。

DOI：
发表时间：
2014-12
期刊：
影响因子：
5.6
作者：
Luque;Ananth, Cande V;Sanchez, Sixto E;Qiu, Chun;Hernandez;Valdimarsdottir, Unnur;Gelaye, Bizu;Williams, Michelle A
通讯作者：
Williams, Michelle A

Placental genetic variations in circadian clock-related genes increase the risk of placental abruption.

胎盘生物钟相关基因的遗传变异会增加胎盘早剥的风险。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Qiu, Chunfang;Gelaye, Bizu;Denis, Marie;Tadesse, Mahlet G;Enquobahrie, Daniel A;Ananth, Cande V;Pacora, Percy N;Salazar, Manuel;Sanchez, Sixto E;Williams, Michelle A
通讯作者：
Williams, Michelle A