Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly (STOP BLOQ)

监测和治疗以预防胎儿房室传导阻滞可能很快发生（STOP BLOQ）

• 批准号: 10440476
• 负责人: Jill P Buyon
• 金额: $ 70.32万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440476
• 关键词: Address; Anti-Inflammatory Agents; Antibody titer measurement; Atrioventricular Block; Autoantibodies; Biological Process; Birth; Bradycardia; Clinical; Colorado; Data; Detection; Dexamethasone; Disease; Early treatment; Echocardiography; Educational process of instructing; Electrocardiogram; Endocardial Fibroelastosis; Ensure; Equipoise; Event; Extranodal; Feedback; Fetal Heart Rate; Fetal Monitoring; Fetus; Fibrosis; Frequencies; Guidelines; Health Benefit; Healthcare; Heart; Heart Diseases; Heart Injuries; Home; Hour; IgG Receptors; Incidence; Inflammation; Inflammatory; Intravenous Immunoglobulins; Mediating; Monitor; Morbidity - disease rate; Mothers; Multicenter Trials; Myocardial dysfunction; National Institute of Child Health and Human Development; Natural History; Outcome; Participant; Pathogenesis; Perinatal mortality demographics; Phase; Placebos; Placenta; Pregnancy; Public Health; Registries; Reporting; Research; Research Personnel; Risk; Sample Size; Second Pregnancy Trimester; Site; Survivors; System; Techniques; Testing; Universities; Woman; arm; cardiac pacing; disability; effusion; evidence base; falls; fetal; heart rhythm; interdisciplinary collaboration; medical schools; millisecond; mortality; network models; novel; prenatal; prenatal testing; prevent; primary outcome; programs; prospective; recruit; rheumatologist; screening; side effect; standard of care; support network; time interval

ABSTRACT Fetal complete (i.e., 3°) atrioventricular block (AVB), identified in the 2nd trimester in an otherwise normally developing heart, is almost universally associated with maternal anti-Ro autoantibodies and carries a high morbidity and mortality. It has been speculated that full expression of conduction disease results in orderly progression from normal rhythm (NR) to 1° AVB [prolonged AV interval assessed by echocardiogram (echo)], to 2° AVB (irregular cardiac rhythm or bradycardia), culminating in 3° AVB. Identification of a transition period, marked by an irregular rhythm and/or bradycardia, may be the only window of opportunity for treatment to restore NR. Thus, current surveillance employing weekly echos would fall short. We have now shown that daily fetal heart rate and rhythm monitoring (FHRM) by the mother with confirmation of abnormal findings by echo is feasible and affords rapid and successful treatment with no cases of AVB missed. The proposal combines expertise of fetal cardiologist Bettina F. Cuneo, MD (University of Colorado–Denver), rheumatologist Jill P. Buyon, MD (NYU School of Medicine), and 33 sites, to address the hypotheses that early treatment is critical, FHRM reduces the need for weekly echos, and surveillance can be limited to mothers with high-titer antibodies. This prospective trial involves three sequential Steps: 1) Screening for high titer anti-Ro60 or Ro52 centrally in Dr. Buyon's lab; 2) Surveillance by FHRM 3X daily and weekly echo; 3) Treatment of 2° AVB identified by FHRM confirmed by echo. FHRM supported by echo will be leveraged to affirm the efficacy of rapid treatment of 2° AVB and incidence/outcome of AV interval prolongation as well as extra-nodal disease. By identifying 850 high-titer anti-Ro pregnancies in Step 1, FHRM in Step 2, and a single arm multicenter trial in Step 3, Aim 1 will determine whether expeditious treatment of 2° AVB restores NR. Mothers detecting an abnormal FHRM confirmed to be 2° AVB will be treated in ≤12 hours of detection with a potent dual anti-inflammatory approach, dexamethasone and IVIG, the primary outcome being percentage of treated fetuses whose rhythm regresses to NR. A sample size of 30 fetuses with 2° AVB ensures at least 80% power to detect an increase in the rate of reversal to NR from 25% (historical control rate) to 50% with treatment. Women with low-titer anti-Ro will not enter the Step 2-FHRM phase, but birth ECGs will be collected. Aim 2 assesses the incidence and natural history of a fetal prolonged AV interval ≤170 milliseconds (ms). Treatment of AV intervals >170ms will also be evaluated. Aim 3 assesses the incidence and outcome of fetuses with isolated extra-nodal cardiac disease. Impact: Strong preliminary data, interdisciplinary collaboration and national expertise support our application of the NICHD “Consortium Model” Network in providing a unique opportunity to reverse inflammatory/fibrotic sequelae of anti-Ro thereby preventing lifelong disability. It is anticipated that this study will decrease 3° AVB, yield evidence-based management guidelines, set precedent for universal pre-natal screening for anti-Ro, reduce costlier echo surveillance, and empower mothers in their own health care.

抽象的 胎儿完整（即3°）室内室（AVB），在第二个孕期中鉴定在其他正常情况下 发育心脏，几乎与母体抗罗自动抗体相关，并且具有很高的 发病率和死亡率。据推测，传导疾病的完全表达会有序地产生 从正常节奏（NR）到1°AVB的进展[通过超声心动图评估的延长AV间隔]，到 2°AVB（心律不规则或心动过缓），最终以3°AVB为顶。识别过渡期， 以不规则的节奏和/或心动过缓标记，可能是恢复治疗的唯一机会窗口 nr。那是当前使用每周回声的监视将不足。我们现在已经表明了每日胎儿 母亲的心率和节奏监测（FHRM）通过Echo确认异常发现为 可行的，可以快速而成功的治疗，而不会错过AVB病例。该提案结合在一起 胎儿心脏病学家Bettina F. Cuneo，医学博士（科罗拉多大学 - 丹佛分校），风湿病学家Jill P. 马里兰州Buyon（纽约大学医学院）和33个地点，以解决早期治疗至关重要的假设 FHRM减少了对每周回声的需求，并且监视可能仅限于具有高细胞抗体的母亲。 该前瞻性试验涉及三个顺序步骤：1）筛选高滴度抗Ro60或RO52在中心 Buyon博士实验室； 2）FHRM每天3倍和每周回声进行监视； 3）FHRM鉴定的2°AVB处理 由Echo确认。 ECHO支持的FHRM将被利用以遭受2°AVB快速治疗的效率 以及AV间隔延长的事件/结局以及节点疾病。通过识别850个高速公路 步骤1中的抗RO妊娠，步骤2中的FHRM和步骤3中的单臂多中心试验，AIM 1将确定 2°AVB的迅速治疗是否还原NR。发现异常FHRM的母亲证实 2°AVB将在≤12小时的检测中以潜在的双重抗炎方法进行处理， 地塞米松和IVIG，主要结果是节奏回归为的胎儿的百分比 nr。 2°AVB的样本量为30个胎儿，可确保至少80％的功率检测率的增加 通过治疗，将NR从25％（历史控制率）逆转到50％。有低音抗反罗的妇女不会 输入步骤2-FHRM阶段，但将收集出生率。 AIM 2评估事件和自然 胎儿延长AV间隔≤170毫秒（MS）的历史。 AV间隔> 170ms的处理也将 进行评估。 AIM 3评估孤立的鼻外心脏的胎儿的事件和结果 疾病。影响：强大的初步数据，跨学科合作和国家专业知识支持我们 NICHD“财团模型”网络的应用提供了一个独特的机会来逆转 抗RO的炎症/纤维化后遗症，从而防止终身残疾。预计这项研究将 减少3°AVB，基于证据的管理指南，为通用产前筛查设定了先例 对于反罗，请减少更具昂贵的回声监视，并使母亲在自己的医疗保健中赋予能力。