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

• 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
• 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

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），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、子痫前期和宫内生长受限）的病理生理机制包括子宫胎盘缺血、灌注不足、慢性缺氧和梗死。在此基础上，研究者已经开始将早剥概念化为具有急性和慢性病理生理特征的“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触发AP。AP的病因尚不清楚，尽管先前的研究结果表明一些危险因素和新证据表明AP的发病机制中有重要的遗传成分。目前，对AP的准确预测和预防都是不可能的。我们试图通过在秘鲁利马开展一项大型多中心的AP流行病学研究来增加我们对AP流行病学和病理生理学的理解。我们将采用自匹配病例交叉设计来评估以下因素的急性效应：1)母亲吸烟和饮酒；2)体力消耗；3)性行为；4)跌落或机动车碰撞引起的腹部外伤；5)暴露于亲密伴侣暴力是AP的潜在“触发因素”。AP的风险将在预先指定的危险期进行评估。我们还将采用病例对照复制（两阶段）研究设计，在900对母子早剥病例和900对母子对照中研究影响AP发病机制的遗传变异。我们计划将重点放在特定的基因通路上，包括凝血、纤溶、血小板功能、感染和炎症、血管生成、叶酸代谢以及肾素-血管紧张素系统。在第一阶段，我们将在前半部分样本上使用高密度单核苷酸多态性（SNP）“1536芯片”扫描母婴SNP和SNP单倍型，以寻找与AP相关的基因。我们将选择约200个最相关的候选snp在另一半样本中进行复制。我们假设与第一阶段AP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和习惯性暴露（例如，习惯性饮酒和身体活动）以及酗酒或极端体力消耗等因素的触发效应之间可能的相互作用，揭示对AP病理生理学的新见解。结果还将对AP的遗传遗传基础产生新的见解。总的来说，这些新的见解可能有助于开发AP的初级预防新方法（在公共卫生层面），也可能有助于开发新的治疗方法和诊断方法。

项目成果

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: 10.1371/journal.pone.0156755
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gelaye,Bizu;Sumner,SusanJ;McRitchie,Susan;Carlson,JamesE;Ananth,CandeV;Enquobahrie,DanielA;Qiu,Chunfang;Sorensen,TanyaK;Williams,MichelleA
• 通讯作者: Williams,MichelleA

Placental mitochondrial DNA content and placental abruption: a pilot study.

• DOI: 10.1186/s13104-015-1340-4
• 发表时间: 2015-09-16
• 期刊: BMC research notes
• 影响因子: 1.8
• 作者: Qiu, Chunfang;Sanchez, Sixto E;Williams, Michelle A
• 通讯作者: Williams, Michelle A

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。

• 发表时间: 2013
• 期刊: International journal of molecular epidemiology and genetics
• 作者: Williams,MichelleA;Sanchez,SixtoE;Ananth,CandeV;Hevner,Karin;Qiu,Chunfang;Enquobahrie,DanielA
• 通讯作者: Enquobahrie,DanielA

Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies.

遗传变异和胎盘破裂的风险：全基因组关联研究和全基因组关联研究的荟萃分析。

• DOI: 10.1016/j.placenta.2018.04.008
• 发表时间: 2018-06
• 期刊: Placenta
• 影响因子: 3.8
• 作者: Workalemahu T;Enquobahrie DA;Gelaye B;Sanchez SE;Garcia PJ;Tekola-Ayele F;Hajat A;Thornton TA;Ananth CV;Williams MA
• 通讯作者: Williams MA

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

线粒体生物发生和氧化磷酸化中的胎盘胎盘风险和遗传变异：候选基因关联研究的复制。

• DOI: 10.1016/j.ajog.2018.08.042
• 发表时间: 2018-12
• 期刊: American journal of obstetrics and gynecology
• 影响因子: 9.8
• 作者: Workalemahu T;Enquobahrie DA;Gelaye B;Thornton TA;Tekola-Ayele F;Sanchez SE;Garcia PJ;Palomino HG;Hajat A;Romero R;Ananth CV;Williams MA
• 通讯作者: Williams MA