Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers.

Abstract

BACKGROUND:

Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB).

OBJECTIVES:

Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB.

METHODS:

This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash.

RESULTS:

By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4).

CONCLUSIONS:

These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).

• Authors: Peter Izmirly, Mimi Kim, Deborah M Friedman, Nathalie Costedoat-Chalumeau, Robert Clancy, Joshua A Copel, Colin K L Phoon, Bettina F Cuneo, Rebecca E Cohen, Kimberly Robins, Mala Masson, Benjamin J Wainwright, Noel Zahr, Amit Saxena, Jill P Buyon
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 76 Issue 3 Pg. 292-302 (07 21 2020) ISSN: 1558-3597 [Electronic] United States
• PMID: 32674792 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Autoantibodies
• Enzyme Inhibitors
• Hydroxychloroquine

Topics

• Administration, Oral
• Adult
• Autoantibodies (immunology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (administration & dosage)
• Female
• Fetal Diseases (prevention & control)
• Follow-Up Studies
• Heart Block (congenital, drug therapy, embryology)
• Humans
• Hydroxychloroquine (administration & dosage)
• Infant, Newborn
• Male
• Pregnancy
• Prospective Studies
• Secondary Prevention (methods)