EAGeR Trial - The Effects of Aspirin in Gestation and Reproduction Trial

EGeR 试验 - 阿司匹林对妊娠和生殖试验的影响

• 批准号: 9348238
• 负责人: Enrique F. Schisterman
• 金额: $ 64.72万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9348238
• 关键词: Adverse event; Affect; Age; Ancillary Study; Anovulation; Aspirin; Birth Rate; Blood flow; Blood specimen; Clinical; Collection; Conceptions; Data; Data Reporting; Diagnosis; Dose; Eligibility Determination; Evaluation; Fertility; Fetal Death; Freezing; Gestational Age; Goals; Infertility; Inflammation; Inflammatory; Laboratories; Link; Live Birth; Medical center; Menstrual cycle; Methods; Outcome; Participant; Pathway interactions; Phase; Pilot Projects; Placebos; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Rate; Pregnancy loss; Premature Birth; Procedures; Process; Publishing; Randomized; Recording of previous events; Reporting; Reproduction; Risk; Sex Ratio; Specimen; Spontaneous abortion; Spottings; Time; Tissue Banks; Urine; Validation; Visit; Woman; Work; base; disorder prevention; double-blind placebo controlled trial; failure Implantation; follow-up; meetings; offspring; pregnant; randomized trial; research study; sample collection; secondary outcome

The EAGeR trial was a multi-center, block-randomized, double-blind, placebo-controlled trial conducted across four medical centers in the U.S. from 2007 to 2012. A total of 1228 women ages 18-40 years with up to two documented prior miscarriages and who planned to become pregnant again were randomized for this trial, making the EAGeR trial the largest preconception trial of LDA. Each woman was randomly assigned to 81 mg aspirin daily or placebo beginning prior to conception and continued to 36 weeks gestation in women achieving pregnancy. Participants were block randomized by study center and eligibility stratum, defined based on specific eligibility qualifications: 1) original stratum, women with exactly one documented pregnancy loss <20 weeks gestation during the preceding 12 months; and 2) expanded stratum, women not meeting all criteria for the original stratum, and having 1 or 2 prior pregnancy losses of any gestational age at any time in the past. Participants attended two study visits per menstrual cycle for the first two cycles attempting pregnancy and once per cycle thereafter, which included spot urine and blood sample collection. Follow-up ended after six menstrual cycles attempting pregnancy or, in women becoming pregnant, throughout pregnancy. EAGeR recruitment started in June 2007 and ended in July 2011. Since the completion of EAGeR, Dr. Schisterman and the EAGeR team have completed analysis of the primary (live birth) and secondary trial outcomes (pregnancy rates and pregnancy outcomes, including losses), and examined several ancillary study questions. The primary findings of the trial were published in 2014, reporting that daily LDA did not significantly affect live birth (RR 1.10, 95%CI 0.98, 1.22) or pregnancy loss rates overall. However, among the prespecified original stratum (those with a single recent loss, specifically only one prior pregnancy loss <20 weeks gestation in the previous year) live birth rate was higher in the LDA compared with placebo group (62% LDA vs. 53% placebo; RR 1.17, 95%CI 1.01, 1.37). The pathway through which this effect was evident was not an effect of reducing pregnancy loss, but rather through an increased fecundability (i.e., a shorter time to pregnancy) in this group. Similarly, preterm birth was lower in the LDA group of the original stratum (3.8% LDA vs. 9.7% placebo; RR 0.39, 95%CI 0.16, 0.94). These collective findings lend support to the notion that low-dose aspirin could have favorable effects on fecundity as opposed to reducing pregnancy loss risk after pregnancy is diagnosed, but precise factors to indicate which women may receive benefit remained unclear. Secondary outcomes explored from the EAGeR trial included evaluation of adverse events, anovulation, and offspring sex ratio. Multiple other reports were also published or are in-progress examining different etiologic and clinical questions. In addition, another crucial next phase in examining mechanisms impacted by LDA will include the study of placental specimens collected from a subset of term deliveries in the trial. To this end, a pilot study was conducted 2014-2016 to plan use of the frozen specimens. This pilot effort was composed of experiments aimed at determining the effects of storage and collection methods that were unique to this trial to accomplish large scale, clinical tissue collection, on levels of inflammatory and angiogenic analytes. These data will provide important validation information, as well of laboratory processing standard operating procedures, to conduct analyses on the stored EAGeR specimens and compare our work with previously reported data.

这项急切的试验是一项多中心、随机、双盲、安慰剂对照的试验，于2007年至2012年在美国的四个医疗中心进行。共有1228名年龄在18-40岁之间、有两次有记录的流产史并计划再次怀孕的妇女参加了这项试验，这使这项急切试验成为LDA最大的先入为主试验。每位妇女在受孕前被随机分配每天服用81毫克阿司匹林或安慰剂，对于怀孕36周的妇女继续服用。参与者按研究中心和资格阶层随机分组，根据特定的资格资格定义：1)原始阶层，在过去12个月内恰好有一次有记录的怀孕损失和20周妊娠；2)扩大阶层，妇女不符合原始阶层的所有标准，并且在过去任何时候都有1到2次怀孕损失。参与者在前两个尝试怀孕的周期中每个月经周期进行两次研究访问，之后每个周期进行一次研究访问，包括现场尿液和血液样本采集。随访在尝试怀孕的六个月经周期后结束，或者在怀孕的妇女整个怀孕期间结束。 热切的招聘从2007年6月开始，到2011年7月结束。自AGERGE完成后，Schisterman博士和EIGER团队已经完成了初级试验(活产)和次级试验结果(妊娠率和妊娠结局，包括损失)的分析，并检查了几个辅助研究问题。该试验的初步结果发表于2014年，报告称，每日LDA对活产(RR 1.10，95%CI 0.98，1.22)或总体妊娠失败率没有显著影响。然而，在预先指定的原始阶层(最近一次丢失，特别是前一年仅有一次怀孕丢失和前一年怀孕20周)中，LDA组的活产率高于安慰剂组(62%LDA比53%安慰剂；RR 1.17，95%CI 1.01，1.37)。这种效果明显的途径不是减少妊娠丢失的效果，而是通过增加这一组人的受孕能力(即更短的怀孕时间)。同样，原始地层的LDA组早产较低(3.8%LDA比9.7%安慰剂；RR 0.39，95%CI 0.16，0.94)。这些集体发现支持了这样的观点，即在诊断出怀孕后，小剂量阿司匹林可能会对生育力产生有利影响，而不是降低怀孕损失风险，但表明哪些女性可能受益的确切因素尚不清楚。从急切试验中探索的次要结果包括评估不良事件、无排卵和后代性别比。 研究不同病因学和临床问题的多个其他报告也已发表或正在进行中。此外，检查LDA影响机制的另一个关键的下一阶段将包括研究从试验中足月分娩的子集收集的胎盘标本。为此，2014-2016年进行了一项试点研究，以规划冷冻标本的使用。这项试点工作由实验组成，旨在确定该试验特有的存储和收集方法对炎症和血管生成分析物水平的影响，这些方法是完成大规模临床组织收集的独特方法。这些数据将提供重要的验证信息，以及实验室处理标准操作程序，以对储存的紧急标本进行分析，并将我们的工作与以前报告的数据进行比较。