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

Abstract

Background: Experimental and clinical evidence slupport the role of macrophage Toll-like receptor (TLR) signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). Objectives: Hydroxychloroquine (HCQ), an orally administered TLR 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, two-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 first stage; N=35 second stage). Patients received 400mg 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 and/or 1°CHB at birth and/or skin rash. Results: By intention-to-treat (ITT) analysis, 4/54 evaluable pregnancies resulted in a primary outcome (7.4%; 90%CI:3.4%−15.9%). Since 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous gamma globulin) 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, 4/54 (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 more than 50%, suggesting that this drug be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies.