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.

抽象的 胎儿完全性（即 3°）房室传导阻滞 (AVB)，在妊娠第二个月发现，否则正常 发育中的心脏，几乎普遍与母体抗 Ro 自身抗体相关，并且具有较高的 发病率和死亡率。据推测，传导病的充分表达导致有序 从正常节律 (NR) 进展到 1° AVB [通过超声心动图 (echo) 评估 AV 间期延长]， 2° AVB（心律不规则或心动过缓），最终达到 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 NR。因此，目前采用每周回声的监测是不够的。我们现在已经证明胎儿每天 母亲进行心率和节律监测 (FHRM)，并通过回波确认异常结果 可行，并提供快速、成功的治疗，没有漏掉任何 AVB 病例。该提案结合了 胎儿心脏病学家 Bettina F. Cuneo, MD（科罗拉多大学丹佛分校）和风湿病学家 Jill P. Buyon, MD（纽约大学医学院）和 33 个研究中心，为了解决早期治疗至关重要的假设， FHRM 减少了每周回声的需要，并且监测可以仅限于具有高滴度抗体的母亲。 该前瞻性试验涉及三个连续步骤：1) 集中筛选高滴度抗 Ro60 或 Ro52 Buyon 博士的实验室； 2) 通过 FHRM 3X 每日和每周回波进行监测； 3) FHRM 确定的 2° AVB 的治疗 经回声证实。 echo 支持的 FHRM 将用于确认 2° AVB 快速治疗的疗效 AV 间期延长以及结外疾病的发生率/结果。通过鉴定850个高滴度 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 2° AVB 的快速治疗是否可以恢复 NR。发现异常 FHRM 的母亲证实 2° AVB 将在检测后 ≤12 小时内采用有效的双重抗炎方法进行治疗， 地塞米松和 IVIG，主要结果是接受治疗的胎儿的节律回归到的百分比 NR。样本量为 30 个具有 2° AVB 的胎儿，可确保至少 80% 的功效来检测胎儿比率的增加 通过治疗，NR 从 25%（历史控制率）逆转至 50%。具有低滴度抗 Ro 的女性不会 进入步骤 2-FHRM 阶段，但将收集出生心电图。目标 2 评估发病率和自然发生率 胎儿 AV 间期延长≤170 毫秒 (ms) 的病史。 AV 间隔 >170ms 的治疗也将 进行评估。目标 3 评估胎儿孤立性结外心脏病的发生率和结局 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“联盟模式”网络的应用提供了独特的逆转机会 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 降低 3° AVB，产生循证管理指南，为全民产前筛查开创先例 针对反 Ro，减少昂贵的回声监测，并赋予母亲自己的医疗保健权。