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: 10250529
• 负责人: Jill P Buyon
• 金额: $ 72.48万
• 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/10250529
• 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.

摘要 胎儿完全性(即3°)房室传导阻滞(AVB)，在妊娠中期发现，其他方面正常 发育中的心脏，几乎普遍与母体抗Ro自身抗体有关，并携带高 发病率和死亡率。据推测，传导性疾病的充分表达导致有序 从正常心律(NR)进展到1°AVB[超声心动图(ECHO)评估房室间期延长]，到 2°AVB(心律不齐或心动过缓)，最终为3°AVB。确定过渡期， 以心律不齐和/或心动过缓为特征，可能是治疗恢复的唯一机会之窗 天然橡胶。因此，目前采用每周回声的监测将达不到要求。我们现在已经展示了每天的胎儿 由母亲进行心率和节律监测(FHRM)，并通过ECHO确认异常发现 可行，可提供快速、成功的治疗，没有遗漏AVB病例。该提案结合了 胎儿心脏病专家Bettina F.Cuneo，医学博士(科罗拉多大学丹佛分校)，风湿病专家Jill P. Buyon，MD(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减少了每周回声的需要，监测可以仅限于具有高滴度抗体的母亲。 这项前瞻性试验包括三个连续步骤：1)集中筛选高滴度抗Ro60或Ro52 Buyon博士的实验室；2)FHRM每天和每周3X ECHO监测；3)FHRM确定的2°AVB的治疗 已被ECHO确认。在ECHO的支持下，FHRM将被用来肯定快速治疗2°AVB的疗效 房室间期延长及结外病变的发生率/转归。通过鉴定850高滴度 步骤1中的抗Ro妊娠，步骤2中的FHRM，以及步骤3中的单臂多中心试验，目标1将确定 快速治疗2°AVB能否恢复正常。母亲检测到FHRM异常确认为 BE 2°AVB将在≤中接受12小时检测，并采用有效的双重抗炎方法， 地塞米松和静脉注射丙种球蛋白，主要结果是接受治疗的胎儿心律倒退到 天然橡胶。具有2°AVB的30个胎儿的样本大小确保了至少80%的功率来检测到 经治疗后，完全缓解的比例从25%(历史控制率)降至50%。低滴度抗-Ro的女性不会 进入步骤2-FHRM阶段，但将收集分娩心电。目的2评估发病率和自然 胎儿房室间期延长的病史≤为170毫秒。房室间期&gt；170ms的处理也将 被评估。目的3评估胎儿孤立性结外心脏的发生率和结局 疾病。影响：强大的初步数据、跨学科协作和国家专业知识支持我们 NICHD“联盟模式”网络在提供逆转的独特机会方面的应用 抗Ro的炎症/纤维化后遗症，从而防止终生残疾。预计这项研究将 减少3°AVB，制定循证管理指南，开创普遍产前筛查先河 对于抗Ro，减少昂贵的ECHO监测，并在自己的医疗保健中增强母亲的能力。