Background/Purpose: Based on encouraging bench to bedside results including experimental evidence supporting Toll-like receptor signaling in the pathogenesis of CHB, a case control study demonstrating CHB risk reduction in hydroxychoroquine (HCQ) exposed fetuses of anti-Ro positive SLE women, and a historical cohort study supporting a reduction in recurrence rate, an open label single arm Phase 2 clinical trial was initiated to evaluate whether HCQ reduces the CHB recurrence rate (π) below the historical recurrence rate of 18%.

Methods: A two-stage trial design (N=19 first stage; N=54 second stage) using Simon’s optimal approach was employed to allow for early stopping due to absence of treatment efficacy. The null hypothesis, H₀:π ≥ 18%, would be rejected and HCQ considered efficacious at the end of the trial if ≤ 5 of 54 mothers with anti-Ro and a previous CHB child had a subsequent child with 2^nd or 3^rd degree block (primary outcome). The protocol required HCQ initiation or maintenance at 400mg by 10 wks gestation. Mothers underwent serial echocardiograms, with bloods drawn each trimester and delivery for cord blood to measure antibody and HCQ levels.

Results: Sixty five mothers (all with previous CHB child and anti-Ro52 or Ro60 > 1,000 EU; 47.9% with anti-La; 71.4% White; 47.6% SLE and/or SS; 42.9% started HCQ solely for CHB prevention; 41% prior CHB child died, 3.2% had > 1 CHB child) signed consent. Ten were considered screen failures (2 miscarriages < 12 wks, 7 wherein dating of conception placed HCQ initiation at > 10 wks, 1 given dexamethasone (dex) 1mg at 10 wks) and 1 was lost to follow up before delivery leaving 54 pregnancies evaluable with serial fetal echos and birth or one yr EKG or echo results known. In Stage I, 2/19 fetuses had CHB, and the study proceeded to Stage II. By intention to treat analysis, 4/54 pregnancies resulted in CHB (7.4%; p = 0.02 for H₀), all at 19-20 wks. Three presented with 2^nd degree block, one reverted to NSR at birth following dex and two progressed to 3^rd degree despite dex and IVIG (one electively terminated). One presenting with 1^st degree was treated with dex prophylactically (eliminating this case from evaluating HCQ exposure alone), progressed to 2^nd but reverted to NSR at birth. At 2 yrs, the 2 in NSR had intermittent 2^nd degree on Holter monitor. In 8 mothers potentially confounding medications, IVIG and/or dex, were prescribed after enrollment for lupus flare, cardiac concerns apart from advanced block (APCs, echo brightness, 1^st degree block), and/or physician decision to consider additional prophylaxis. To evaluate HCQ alone, 9 additional mothers were enrolled, one whose fetus developed 3^rd degree block at 19 wks. Including only pregnancies exposed to HCQ alone prior to confirmed 2^nd or 3^rd degree block, 4/54 developed CHB (7.4%; p = 0.02). In total 5/63 pregnancies (7.9%) resulted in advanced block. HCQ levels in the second trimester confirmed a 98% adherence rate. Anti-Ro levels remained > 1,000 EU (considered vulnerable for CHB) throughout pregnancy. No CHB developed in any of the 7 mothers screened out because of low dose or delayed start of HCQ.   

Conclusion: These prospective data from a single-arm clinical trial support that HCQ significantly reduces the recurrence of CHB below the historical rate.  

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-prospective-open-label-preventive-approach-to-congenital-heart-block-with-hydroxychloroquine-patch-study-demonstrates-a-reduction-in-the-recurrence-rate-of-advanced-block/