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 胎儿完整（即，3°）房室传导阻滞（AVB），在妊娠中期发现，在其他方面正常 发育中的心脏，几乎普遍与母体抗Ro自身抗体相关，并携带高水平的 发病率和死亡率。据推测，传导疾病的充分表达导致有序的 从正常心律（NR）进展至1° AVB [通过超声心动图（echo）评估的AV间期延长]，至 2° AVB（心律不齐或心动过缓），最终3° AVB。确定过渡期， 以心律不齐和/或心动过缓为标志的，可能是治疗恢复的唯一机会窗口。 NR.因此，目前的监测采用每周回声将达不到。我们现在已经证明， 由母亲进行心率和节律监测（FHRM），并通过超声心动图确认异常结果， 该方法可行，可提供快速和成功的治疗，无AVB病例漏诊。该提案结合 胎儿心脏病专家Bettina F. Cuneo，MD（科罗拉多-丹佛大学），流变学家Jill P. Buyon，MD（纽约大学医学院）和33个研究中心，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，并且监测可以限于具有高滴度抗体的母亲。 该前瞻性试验包括三个连续步骤：1）集中筛查高滴度抗Ro 60或Ro 52， 博士Buyon实验室; 2）通过FHRM每日和每周3次超声心动图监测; 3）治疗FHRM确定的2° AVB 经echo证实。将利用超声心动图支持的FHRM确认快速治疗2° AVB的有效性 和AV间期延长以及结外疾病的发生率/结局。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，目的1将确定 2° AVB的快速治疗是否恢复NR。检测到异常FHRM的母亲证实， 2° AVB将在检测后≤12小时内采用强效双重抗炎方法进行治疗， 地塞米松和IVIG，主要结局是心律恢复至 NR. 30个2° AVB胎儿的样本量可确保至少80%的把握度来检测AVB发生率的增加 治疗后从25%（历史对照率）逆转至50%。抗Ro抗体滴度低的女性 进入步骤2-FHRM阶段，但将采集出生ECG。目标2评估发病率和自然发病率 胎儿AV间期延长≤170毫秒（ms）的病史。AV间期> 170 ms的治疗也将 被评价。目的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的 应用NICHD“联盟模式”网络，提供一个独特的机会， 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，为普遍产前筛查开创先例 减少昂贵的回声监测，并赋予母亲自己的医疗保健。