Increasing understanding of causes of stillbirth: Is the effect of maternal stress on stillbirth mediated by methylation of stress-related genes?

加深对死产原因的了解：母亲压力对死产的影响是否是由压力相关基因的甲基化介导的？

• 批准号: 10304121
• 负责人: Susannah Hopkins Leisher
• 金额: $ 4.22万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2022-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304121
• 关键词: Address; Area; Attention; Bereavement; Bioinformatics; Biological; Birth; Birth Rate; Candidate Disease Gene; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child Abuse and Neglect; Cohort Studies; Country; DNA Methylation; Data; Ensure; Epidemiology; Epigenetic Process; Ethnic Origin; Etiology; Europe; Event; Exposure to; Family; Fetal Death; Genes; Goals; Health; Iceland; Impairment; Income; Individual; Infant Mortality; Inflammation; International Classification of Diseases; Knowledge; Life; Link; Live Birth; Logistic Regressions; Low Birth Weight Infant; Maternal Exposure; Measures; Mediating; Mediation; Mediator of activation protein; Methods; Methylation; Modeling; Modification; Mothers; NR3C1 gene; National Institute of Child Health and Human Development; Neonatal Mortality; Not Hispanic or Latino; Outcome; Pakistan; Pathway interactions; Physiological; Policies; Population; Poverty; Pregnancy; Pregnancy Outcome; Premature Birth; Prevention; Public Health; Race; Reporting; Research; Research Personnel; Research Priority; Risk; Role; Socioeconomic Status; Stress; Subgroup; Testing; Time; Tissues; Training; Training Support; Unemployment; United Nations; United States; Universities; Vital Statistics; adverse childhood events; adverse pregnancy outcome; age group; aged; biological adaptation to stress; career; case control; cohort; design; epigenetic silencing; epigenome; fetal; fetal loss; improved; inattention; infant death; maternal stress; mortality; perceived stress; perinatal outcomes; population based; prenatal exposure; racial diversity; racism; segregation; skills; stillbirth; stressor; systematic review; therapy development; virtual

PROJECT SUMMARY/ABSTRACT The burden of 2.6 million stillbirths a year places stillbirth on a par with neonatal mortality as a major global public health issue. In the U.S., the stillbirth rate of 6.0 per 1000 total births has consistently exceeded the infant mortality rate, and is higher than the stillbirth rates of 25 other high-income countries. Moreover, there is high racial inequity, with Black families facing a stillbirth rate more than double that of whites. There has been persistent global inattention to stillbirth prevention, and the United Nations’ goal of 12 stillbirths per 1000 births by 2030 is unlikely to be met. The CDC’s vital statistics report on mortality excludes stillbirths, and the CDC only began reporting on causes of stillbirth in 2014. One barrier is limited knowledge on causes. The wide range of stillbirth rates, from 1.3 in Iceland to 43.1 in Pakistan, demonstrates that most stillbirths are not inevitable, yet one-third of stillbirths are unexplained. A recent review of 489,089 stillbirths found a pooled estimate of 32% of stillbirths “unexplained” in high-income countries—nearly 400 times higher than the rate of unexplained infant deaths in the U.S. Limited understanding of causes reduces opportunities for prevention. Stress holds promise as a possible cause, with epidemiological evidence of an association with stillbirth, but no studies have yet assessed biological plausibility. One potential mechanism is epigenetic silencing of stress-related genes through DNA methylation. Using a nested case-control design with data from a racially diverse population-based cohort, the NICHD-founded Stillbirth Collaborative Research Network (SCRN), this study will assess whether the effect of maternal stress on stillbirth is mediated by methylation of stress-related genes. Study aims are to: (1) test models for the effect of stress (as measured by socioeconomic status, childhood maltreatment, and significant life events) on stillbirth in the SCRN population (663 stillbirths, 1,439 live births) and a subgroup of 66 non-anomalous full-term stillbirths and 132 livebirths; (2) use causal mediation analysis to assess evidence for mediation by methylation of stress-related candidate genes in placental tissue; (3) carry out exploratory assessment of modification of these effects by race/ethnicity; and (4) use an agnostic approach to further assess mediation by epigenome-wide methylation. By demonstrating biological plausibility, the study could contribute to knowledge of preventable causes, highlight the role of stress in inequity in stillbirth rates, generate new hypotheses, and inform the development of interventions at individual and policy levels to reduce stillbirth numbers. The proposed aims will directly contribute to the NICHD’s goals of improving pregnancy outcomes and identifying exposures to explain fetal loss, as well as the high-priority research area of addressing the burden of stillbirth. The proposed training plan will be delivered within Columbia University, one of the world’s preeminent research universities, providing the applicant with skills in epigenetics, bioinformatics, and advanced methods that will, with an outstanding sponsor team, ensure successful completion of the study and the applicant’s transition to a career as an independent researcher focused on stillbirth prevention.

项目总结/摘要 每年260万死产的负担使死产与新生儿死亡率不相上下，成为全球主要的公共卫生问题。 健康问题。在美国，死产率为每1 000名新生儿中6.0人，一直超过婴儿死亡率。 死亡率，高于其他25个高收入国家的死胎率。此外，高 种族不平等，黑人家庭面临的死胎率是白人的两倍多。出现 全球对死产预防的持续忽视，以及联合国每1000例分娩中12例死产的目标 到2030年，不太可能实现。疾病预防控制中心关于死亡率的生命统计报告不包括死产，疾病预防控制中心只 2014年开始报告死胎原因。一个障碍是对原因的了解有限。的广泛 死产率从冰岛的1.3到巴基斯坦的43.1，表明大多数死产并非不可避免， 三分之一的死产原因不明。最近对489，089例死产的回顾发现， 高收入国家“原因不明”的死产率比原因不明的婴儿高出近400倍 对原因的了解有限，减少了预防的机会。压力带来希望 作为一个可能的原因，流行病学证据表明与死产有关，但还没有研究表明， 评估生物相容性。一个潜在的机制是通过基因沉默的表观遗传压力相关基因， DNA甲基化使用嵌套病例对照设计，数据来自种族多样性人群队列， NICHD成立的死产合作研究网络（SCRN），这项研究将评估是否 母亲应激对死胎的影响是通过应激相关基因的甲基化介导的。研究目的是 （1）测试压力影响的模型（通过社会经济地位，童年虐待， 在SCRN人群（663例死产，1，439例活产）和66例亚组中， 非异常足月死产和132例活产;（2）使用因果中介分析评估以下证据： 通过胎盘组织中应激相关候选基因的甲基化进行介导;（3）进行探索性的 通过种族/民族评估这些影响的改变;以及（4）使用不可知论方法进一步评估 通过表观基因组范围的甲基化来介导。通过证明生物相容性，这项研究可以有助于 了解可预防的原因，强调压力在死产率不平等中的作用， 新的假设，并为制定个人和政策层面的干预措施提供信息， 死胎数拟议的目标将直接有助于NICHD改善怀孕的目标 结果和识别暴露，以解释胎儿丢失，以及解决高优先级的研究领域 死产的负担拟议的培训计划将在哥伦比亚大学内实施，哥伦比亚大学是世界上 卓越的研究型大学，为申请人提供表观遗传学，生物信息学和高级 与优秀的申办者团队合作，确保成功完成研究和 申请人过渡到职业生涯作为一个独立的研究人员专注于死产预防。