Summary

Eligibility
for females ages 18 years and up (full criteria)
Location
at San Francisco, California and other locations
Dates
study started
estimated completion
Principal Investigator
Anita Mood-Grady, MD
Photo of Anita Mood-Grady
Anita Mood-Grady

Description

Summary

Fetal complete (i.e., third degree, 3°) atrioventricular block (AVB), identified in the 2nd trimester of pregnancy in an otherwise normally developing heart, is almost universally associated with maternal anti-Ro autoantibodies and results in death in a fifth of cases. To date treatment of 3° AVB has been ineffective in restoring normal rhythm (NR) which may be because current surveillance is limited to once- weekly fetal echocardiograms. It is hypothesized that there may be a vital transition period of several hours in which incomplete block (2° AVB) may be successfully treated avoiding fully advanced irreversible 3° AVB. To optimize the likelihood of timely detection of the transition period this study comprises three steps: 1) to risk stratify for high titer anti-Ro antibodies, which are necessary but not sufficient to develop fetal AVB; 2) to empower mothers to identify 2° AVB by using fetal heart rate and rhythm monitoring (FHRM) at home, and 3) to rapidly treat mothers who detect an abnormality by monitoring with an urgent echocardiogram that confirms 2° AVB with the hope of reversing 2° AVB before it becomes permanent (3° AVB). In addition, it will be determined if FHRM reduces the need for weekly echoes. Although mothers with low titer anti-Ro will not be continued in Step 2 and therefore not followed by FHRM, birth ECGs will be collected to confirm that low titer antibodies do not confer risk. It is anticipated that this study will provide an evidenced based surveillance strategy for those mothers at high risk of having a child with 3° AVB.

Details

Fetal complete (3°) atrioventricular block (AVB), identified in the 2nd trimester in an otherwise normally developing heart, is almost universally associated with maternal anti-Ro autoantibodies, which transcytose the placenta via the trophoblastic IgG receptor, FcγRn. The burden of 3° AVB is considerable: perinatal mortality of 18% exceeds that for all non-cardiac congenital anomalies combined, and almost all survivors require lifelong cardiac pacing with its associated complications. It has been speculated that full expression of conduction disease occurs by sequential fetal 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. Fetal heart rate and rhythm monitoring (FHRM) suggests a time interval of ~12 hours for the transition from NR to 3° AVB, albeit the culprit biologic processes (inflammation leading to fibrosis) likely initiate prior to clinical detection. Anecdotal evidence suggests this transition period, marked by an irregular rhythm and/or bradycardia, may be the only window of opportunity for anti-inflammatory treatment to restore NR.

A barrier to preventing progression to 3° AVB is the absence of a technique to accurately surveil for the precipitate transition from NR to 3° AVB. Surveillance limited to weekly echos (current standard of care) may be too infrequent to detect this transition period when treatment is most likely to be effective. We have now obviated this obstacle and shown that ambulatory FHRM by the mother at home with confirmation of abnormal findings by echo is not only feasible but may afford rapid treatment restoring NR. Combining results from studies comprising 275 anti-Ro+ pregnancies, 87% completed monitoring with a false positive rate of 5%. In 4 cases of 2° AVB identified by FHRM and treated <12h, AVB reversed. Remarkably, no cases of 2° or 3° AVB were missed, suggesting mothers can recognize abnormal FHRM, reducing or precluding the need for weekly echos.

The proposed project combines the expertise of fetal cardiologist Bettina F. Cuneo, MD, initiator and PI of the FHRM program, and rheumatologist Jill P. Buyon, MD, founder/director of the largest extant registry of anti-Ro-mediated AVB, whose research on the pathogenesis supports a fetal inflammatory component associated with high-titer antibodies. Participants will be referred from 35 sites in 3 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. Feasibility of FHRM supported by weekly echo of high-autoantibody-titer mothers will be leveraged to address the efficacy of expeditious (<12 h after detection) treatment of 2° AVB as well as the incidence/outcome of AV interval prolongation and extra-nodal disease.

Keywords

AVB - Atrioventricular Block Fetal AVB Atrioventricular Block Dexamethasone IVIG

Eligibility

You can join if…

Open to females ages 18 years and up

  1. Provision of signed and dated informed consent form
  2. Stated willingness to comply with all study procedures and availability for the duration of the study
  3. Be <18 weeks pregnant at the time of enrollment
  4. Titer of anti-Ro 52 or 60 antibodies ≥1,000 EU
  5. Any positive titer of anti-Ro if a history of a previously affected child
  6. Ability to take oral medication and be willing to adhere to the dexamethasone and IVIG protocols.
  7. Ability to perform Doppler fetal heart rate and rhythm monitoring in the ambulatory setting,
  8. Ability to send an audiotext message by cell phone therefore the participant will be informed that they need a phone with texting capabilities. Located within 6 hours drive of the participating pediatric cardiology site
  9. Be ≥18 years of age

You CAN'T join if...

  1. Multi-fetal pregnancy
  2. Known allergic reactions to components of IVIG, or dexamethasone or maternal IgA deficiency
  3. Fetal conduction system disease already present in the current pregnancy
  4. Any women who in the opinion of the investigator cannot understand the consent form or be able to perform thrice daily home monitoring or recognize an abnormal fetal heart rate or rhythm
  5. Women prisoners
  6. Treatment with >20 mg/prednisone q day or with any dose of fluorinated steroids at enrollment

Locations

  • University of California-San Francisco not yet accepting patients
    San Francisco California 94143 United States
  • Stanford University not yet accepting patients
    Palo Alto California 94305 United States

Lead Scientist at UCSF

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
NYU Langone Health
ID
NCT04474223
Phase
Phase 3
Study Type
Interventional
Last Updated