Timely fetal heart block treatment studied in patients with lupus

BY FRIEDA WILEY, PHARMD


Frequently monitoring fetal heart rate and rhythm to detect congenital heart block (CHB) during pregnancy in women with certain maternal autoantibodies – many of whom have lupus – may prevent fetal and neonatal death. Researchers have made pinpointing the ideal timeframe to detect and treat the condition the focus of a new study.

“We don’t know what level of surveillance is necessary or sufficient for protecting the fetal heart,” said Joshua Copel, MD professor of obstetrics, gynecology, and reproductive sciences and pediatrics at Yale University, New Haven, Conn. “This trial could give us insight on detection of early signs of heart block and efficacy of treatment.”

The study, called Surveillance and Treatment to Prevent Fetal Atrioventricular Block Likely to Occur Quickly, or STOP BLOQ, is an ongoing clinical trial in pregnant women who carry autoantibodies that may predispose their fetus to congenital cardiovascular complications. The trial aims to narrow the timeline gap between detection of abnormal fetal heart rate and rhythm and its treatment to improve fetal and neonatal outcomes. Dr. Copel is an investigator at 1 of 36 centers participating in the trial.


Dr. Joshua Copel

Echocardiography in an anti-SSA and anti-SSB positive mother shows complete heart block and a thick and echogenic heart in a fetus at 33 weeks, with an atrial rate of 125 bpm and ventricular rate of 50 bpm.
Courtesy of Shifa Turan, MD, of the Fetal Heart Program, University of Maryland School of Medicine


Preventing poor outcomes from fetal CHB

Fetuses stand about a 1:10,000 chance of developing complete, or third-degree, CHB, also known as complete atrioventricular (AV) block, which may prove fatal. Fetal complete CHB is most often associated with maternal anti-Ro and La antibodies, which occur in approximately 1% of all pregnancies, including some women with rheumatologic disorders such as systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, and RA.


Dr. Anthony Sciscione
“It’s very challenging for the provider and parents when we are managing pregnant women who are positive for the anti-Ro/anti-Sjögren syndrome A [SSA] antibody because of the potential risk for a permanent fetal congenital heart block,” said Anthony Sciscione, DO, director of ChristianaCare’s Delaware Center for Maternal and Fetal Medicine and director of ChristianaCare’s ob.gyn. residency program in Newark, Del. “Unfortunately, the anti-SSA antibody can pass the placenta easily and potentially attack the electrical system of the fetal heart, which potentially leads to permanent damage to the electrical conducting system of the fetal heart.”

Data compiled from previous fetal heart rate monitoring (FHRM) studies suggest that the fetal heart undergoes an approximate 12-hour transitional period from normal heart rate and rhythm to third-degree CHB – noted by arrhythmia with or without bradycardia. The ultimate goal of the STOP BLOQ trial is to detect and treat fetal heart abnormalities during the transitional phase before CHB becomes irreversible and death occurs.

“For years, we have had the problem of figuring out who is at risk for fetal heart complications among those with anti-Ro/SSA antibodies, especially since, in those without a prior affected child, the risk of problems is only 1%-2%,” Dr. Copel said in an interview.

Frequent fetal heart rate monitoring needed

Current guidelines from the American College of Rheumatology recommend monitoring pregnant women who have anti‐Ro/SSA and/or anti‐La/SSB antibodies once a week beginning at weeks 16-18 of pregnancy, but data indicate weekly monitoring proves ineffective because it frequently missing detecting heart rhythm abnormalities within the 12-hour transitional period.

Even if the fetus survives, the neonate’s heart may have undergone significant damage from antibody attack, according to Dr. Sciscione. As a result, treatment may require placement of a permanent pacemaker after birth to correct the imperfect electrical system in the neonate’s heart.

Unlike the current guideline, the STOP BLOQ enrollees will monitor fetal heart rate three times a day.

STOP BLOQ continues the work of previous studies

Recent studies have yielded strong evidence pointing to the need to proactively treat CHB in anti-Ro/SSA-positive women who experienced CHB-related complications in a previous pregnancy but have left knowledge gaps regarding treatment safety and the ideal timeline for administering treatment. For example, the PATCH study showed that administering hydroxychloroquine, a drug commonly used in lupus management, to anti-Ro/anti-SSA pregnant mothers with lupus reduced the risk of CHB. However, chronic hydroxychloroquine therapy comes with risk for undesirable side effects, such as irreversible retinal damage, torsades de pointes, neuropathy, and blood abnormalities.

A single-arm, open-label study, STOP BLOQ began on August 1, 2020, and will enroll an estimated 1,300 participants in 36 sites around the country. The primary endpoint is the percentage of second-degree CHB in patients with normal rhythm (defined as 1:1 AV conduction) at birth. Investigators will measure three secondary endpoints: the percentage of second-degree CHB subjects who maintain normal sinus rhythm at 1 year of age, the percentage of subjects with AV intervals that exceed 170 milliseconds with normal rhythm at birth, and the incidence of isolated extra-nodal cardiac disease. The primary study completion date is set for August 1, 2025, and the secondary completion date is Jan. 1, 2026.


Ductus venosus waveform in the setting of complete congenital heart block, with no regular ventricular systole (S), ventricular diastole (D), and atrial contractions (“a" wave).
Courtesy of Shifa Turan, MD, of the Fetal Heart Program, University of Maryland School of Medicine

Enrollees must be women who are aged at least 18 years and are less than 18 weeks pregnant at the time of enrollment with a titer of anti-Ro52 or anti-Ro60 antibodies of at least 1,000 EU. Women with any positive anti-Ro titer and who previously have given birth to a child with AVB will also be included. Enrollees are required to take oral medication and adhere to dexamethasone and intravenous immunoglobulin (IVIg) protocols. Expectant mothers must also be able to perform Doppler ultrasound fetal heart rate and rhythm monitoring in an ambulatory setting and live within a 6-hour drive of pediatric cardiology facility participating in the study to ensure they can receive timely treatment if they detect an abnormality.

The study excludes women with multifetal pregnancies, maternal IgA deficiency, fetal conduction system disease already present in their current pregnancy, and known allergic reactions to ingredients found in IVIg or dexamethasone.

The study’s primary investigator, Jill Buyon, MD, and colleagues designed the study to have three phases. Each phase will address several key issues related to the development of anti-Ro-mediated CHB. The first step seeks to prospectively identify whether the titer of anti-Ro antibody influences risk and its clinical relevance. For example, an anti-Ro60 or anti-Ro52 titer that falls below the current titer threshold of 1,000 units could indicate substantial negative predictive value, therefore eliminating the need for FHRM. Women whose titers exceed the threshold advance to the second stage of the study in which they self-monitor with Doppler ultrasound three times a day. Mothers who detect an abnormal heart rate or rhythm should visit the clinic for an urgent diagnostic echocardiogram.

“This step will help discern whether women can be empowered to identify an abnormality and with the hope of decreasing the need for more time consuming and costly serial echocardiograms,” said Dr. Buyon, a rheumatologist at New York University.


Dr. Jill Buyon
In cases where a second-degree heart block is identified, the third step will entail the mothers undergoing immediate treatment. Dr. Buyon said this step determines whether heart block detected within a rapid time frame is reversible with dexamethasone and IVIg.

Having a titer that falls below the threshold does not preclude a pregnant woman with lupus from monitoring. Dr. Buyon noted that women who have low antibody titers and do not progress to step two should have standard of care monitoring, as researchers will not fully understand the importance of titer until after the completion of the study. At the end of the study, EKGs will be obtained from the fetuses of women who remained in step one.

“This study will require a significant effort from the patients as well the medical teams taking care of them,” Dr. Buyon said. “While the disease is rare, it can be devastating to the fetus and the child, so a simple, safe surveillance method would be great to have.”

Ultimately, time will tell how these efforts pay off.

The STOP BLOQ trial is sponsored by NYU Langone Health.