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

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.

Grant Number: 5R01HD100929-05
NIH Institute/Center: NIH
Principal Investigator: Jill Buyon