Women with autoimmune disease are at risk of delivering infants with congenital heart block (CHB) and the likelihood is significantly higher in subsequent deliveries than in first-time births. The Preventive Approach to Congenital Heart Block With Hydroxychloroquine (PATCH) trial suggests that hydroxychloroquine — a drug much talked-about recently in the context of the COVID-19 pandemic — may be of benefit for secondary prevention.
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“This is a promising study regarding secondary prevention of congenital heart block,” says Jeff Chapa, MD, Head of the Section of Maternal-Fetal Medicine in Cleveland Clinic Children’s Hospital Department of Obstetrics and Gynecology, who did not participate in the study.
“Pregnant patients with autoimmune disease, including systemic lupus erythematosus, Sjogren’s disease and similar conditions, should be screened for the presence of anti-SSA/Ro and anti-SSB/LA antibodies,” Dr. Chapa explains. “The risk for development of heart block is 2% when anti-SSA is present, and 3% when both anti-SSA and anti-SSB antibodies are present. The recurrence risk is roughly 18% for these patients.”
“Patients with these antibodies are followed closely with frequent assessment of fetal heart rate through the second trimester, when congenital heart block typically occurs. Patients with autoimmune disease are also at risk for pregnancy complications, including preeclampsia, fetal growth restriction and iatrongenic preterm delivery,” Dr. Chapa continues.
Potential for secondary prevention of congenital heart block
“This paper showed prospectively that hydroxychloroquine may reduce the risk, in pregnancies exposed to anti-SSA/Ro antibodies by more than half,” says Peter Aziz, MD, Interim Chair of Pediatric Cardiology and Director of Pediatric Electrophysiology at Cleveland Clinic Children’s, who did not participate in the study. “It’s somewhat surprising that there is finally something we may be able to do to decrease risk of CHB.”
“To date, there hasn’t been much we’ve been able to do to reduce the risk of recurrence of complete heart block in those later pregnancies,” says Dr. Aziz. “Immunomodulators and steroids have been studied, with no promising effect.”
Published in The Journal of the American College of Cardiology, the results from the PATCH trial show that hydroxychloroquine reduces the recurrence of CHB below the historical rate by more than 50%. According to the authors, the findings suggest that the drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies.
In the study, the dosage of hydroxychloroquine was 400 mg daily, starting before completion of gestational week 10 and continuing through pregnancy. The primary outcome was second- or third-degree CHB any time during pregnancy. Secondary outcomes included isolated endocardial fibroelastosis, first-degree CHB at birth, and skin rash.
Conducted at seven medical centers, the study was open-label and single-arm. Only 54 patients were enrolled, all of whom had a previous pregnancy complicated by CHB and seven of whom had taken hydroxychloroquine in a previously affected pregnancy.
Hydroxychloroquine was selected as a target for the trial because of positive outcomes with it in management of CHB in retrospective research, including a case-control study and a multinational historical cohort study.
The new research was performed in two stages, to allow for early termination due to absence of treatment efficacy. Before a primary outcome, nine mothers were found to have taken a potentially confounding medication (fluorinated glucocorticoids and/or intravenous immunoglobulin). Therefore, the authors recruited nine additional mothers, who followed the identical protocol.
Of the 54 evaluable pregnancies, four resulted in a primary outcome (7.4%; 90% confidence interval [CI] 3.4% to 15.9%). There was also one case of mild endocardial fibroelastosis and there were four cases of cutaneous neonatal lupus.
The researchers measured hydroxychloroquine levels in the patients at least once. During the second trimester, all but one of the levels drawn were >200 ng/mL, confirming adherence. Median baseline titers of anti-Ro60 were similar in the pregnancies with and without CHB.
Very promising study, but a randomized clinical trial will be important
The biggest limitation of the study, according to Dr. Aziz, is its size. “I think this paper could be a game-changer, but the optimism has to be tempered somewhat,” he says. “Being able to reproduce these results and to do so in a randomized trial with a larger patient population will be important.”
Commenting in print on their study, the authors noted the difficulty of performing a randomized trial in this population because mothers with a previous child with CHB might be unwilling to agree to randomization to observation if a potentially effective therapy is available. It might also be unethical to discontinue hydroxychloroquine in pregnancy in a patient taking it for systemic lupus erythematosus because the drug is recommended in that setting to prevent disease flares.
Nevertheless, says, Dr. Aziz, “these data are suggestive enough that I think hydroxychloroquine will be adopted as a therapy for reduction of recurrence of CHB in pregnancies exposed to anti-SSA/Ro antibodies. It should be considered in subsequent pregnancies in these mothers.”