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

J Am Coll Cardiol. 2020 Jul 21;76(3):292-302. doi: 10.1016/j.jacc.2020.05.045.


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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Autoantibodies
  • Enzyme Inhibitors
  • Hydroxychloroquine

Supplementary concepts

  • Congenital heart block

Associated data

  • ClinicalTrials.gov/NCT01379573