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

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

Research output: Contribution to journalArticlepeer-review

83 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)292-302
Number of pages11
JournalJournal of the American College of Cardiology
Issue number3
StatePublished - Jul 21 2020


  • anti-SSA/Ro antibodies
  • congenital heart block
  • hydroxychloroquine
  • neonatal lupus
  • prevention

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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