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.

NARRATIVE While anti-SSA/Ro-associated fetal complete (i.e., 3°) atrioventricular block (AVB), identified in the 2nd trimester in an otherwise normally developing heart, is fatal in a fifth of cases and for those who survive requires lifelong pacing, reversal of incomplete block is possible but challenging to identify given only once weekly echocardiographic surveillance. This study comprises three steps: 1) screening anti-Ro positive mothers for high-titer antibodies which are thought to confer greater risk of fetal AVB; 2) teaching mothers with high titer anti- Ro to monitor the fetal heart rate and rhythm at home and arrange immediate feedback on perceived abnormalities; 3) treating fetuses whose mothers detect abnormal monitoring confirmed to be incomplete AVB by echocardiogram. The purpose of our study is to find out whether the level of anti-Ro/SSA can predict fetuses at greatest risk, if mothers can themselves identify reversible fetal cardiac injury by home monitoring, whether expeditious treatment of fetal incomplete AVB can restore normal rhythm, and finally if weekly echocardiographic testing is necessary to surveil for AVB.