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).

Keywords: anti-SSA/Ro antibodies; congenital heart block; hydroxychloroquine; neonatal lupus; prevention.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

CONSORT diagram of PATCH study enrollment. In 13 enrolled mothers, despite being on 400mg HCQ by 10 weeks, consents were signed after 10 weeks, 11 before the first echocardiogram was performed. Two of these 13 agreed to be in the study prior to the first echo and taking 400mg HCQ, but consents were signed after the first echocardiogram. Dex=dexamethasone; HCQ=hydroxychloroquine; ITT=intention-to-treat; IVIG=intravenous immunoglobulin; PP=per-protocol

Central Illustration.

Prevention of recurrent anti-SSA/Ro-associated congenital heart block with hydroxychloroquine: two-stage design with results for intention-to-treat and per-protocol analyses.