Preventive Approach to Congenital Heart Block With Hydroxychloroquine

Inclusion Criteria

• Mothers must have anti-Ro and/or anti-La Ab documented in the NYU immunology laboratory (CLIA-approved), which utilizes an ELISA as well as reactivity on ELISA to at least one of three recombinant antigens (48La, 52Ro, 60Ro, JB laboratory).
• Mothers must have a previous child with cardiac NL, defined herein as: the presence of heart block (1st, 2nd, or 3rd degree) documented by electrocardiogram (EKG), echocardiogram, pacemaker, or statement in the medical record, and/or; presence of cardiac injury, which specifically includes autopsy evidence of a mononuclear infiltrate in the endocardium, myocardium, and pericardium and/or EFE on echocardiogram always associated with cardiac dysfunction. In PITCH, we included women with a prior child with rash; however, recent data generated from the RRNL suggest that recurrence of CHB following rash is 11%, not 18% [34]. Thus, inclusion of previous rash could lead to a falsely lowered recurrence rate, and will therefore be excluded.
• Intrauterine pregnancy ≤10 weeks.
• Mother may be taking ≤20 mg prednisone because, in our experience, CHB has developed in the presence of this dose.
• Mother may be asymptomatic, or have a rheumatic disease such as SLE or SS. Maternal health status has not been considered an influence on the development of CHB.
• Mother may or may not already be taking HCQ. This latter point was discussed with Dr. Nathalie Costedoat-Chalumeau, who has published extensively on measurement of HCQ. While it might be optimal for the mothers anticipating enrollment in the study to all have been on HCQ prior to conception, this is impractical. Some may never achieve pregnancy and not want to take HCQ unless they conceive (especially those asymptomatic). On the other hand, women with SLE are likely to already be on HCQ and it would limit enrollment to exclude these patients if all must initiate HCQ only at enrollment in the first trimester. Although the accepted dogma is that HCQ requires several months for maximal efficacy in treating rheumatic disease, it is unknown whether this would apply to transplacental passage or fetal levels (which are impossible to measure). Dr. Costedoat-Chalumeau suggests that HCQ is probably a three compartment model which includes the circulation, tissues and cells. In the circulation, the half life is approximately 7 days and in the tissues, it is 40 days. In Dr. Costedoat-Chalumeau's experience, steady state blood levels of HCQ are achieved in 4-6 weeks. Thus, dosing the mother no later than 10 weeks gestation should provide sufficient fetal exposure before the vulnerable period of CHB which is generally accepted to span 18-24 wks. Furthermore, the placenta has to be formed for HCQ to gain access to the fetus and it may be effective quickly for the biology we are considering.

Exclusion Criteria

• Mother does not have Ab to Ro or La.
• Identification of any of the following structural lesions considered causal for CHB, i.e., those that could account for block because of fibrous disruption between the atrium and AV node or due to absence of the penetrating bundles of the AV node:
• atrioventricular septal defects;
• b) single ventricle
• c) developmental tricuspid valve disease;
• d) L-transposition of the great arteries;
• e) heterotaxia.
• Mother is taking any glucocorticoids. Although unlikely to be preventative, the use of steroids may confound the interpretation of results. The final point of intense discussion centered around whether another exclusion should be the use of HCQ in the first pregnancy in which CHB occurred. While one could argue that in these mothers HCQ was not effective and perhaps will not be again, this assumption remains speculative and thus prior absence of efficacy of HCQ will not constitute an exclusion criteria.