Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation

Abstract

Background: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine is being considered as prophylaxis and treatment of coronavirus disease-19 (COVID-19). Although hydroxychloroquine is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematosus and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy.

Methods: To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal ECGs and hydroxychloroquine blood levels were available in a recently completed study evaluating the efficacy of hydroxychloroquine 400 mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro (anti-Sjögren's Syndrome A/Ro) antibodies.

Results: Forty-five ECGs were available for corrected QT interval (QTc) measurement, and levels of hydroxychloroquine were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of hydroxychloroquine and the neonatal QTc (R=0.02, P=0.86) or the mean of hydroxychloroquine values obtained throughout each individual pregnancy and the QTc (R=0.04, P=0.80). In total 5 (11% [95% CI, 4%-24%]) neonates had prolongation of the QTc >2 SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal.

Conclusions: In aggregate, these data provide reassurances that the maternal use of hydroxychloroquine is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01379573.

Keywords: COVID-19; heart block; hydroxychloroquine; incidence; pregnancy.

Figures

Figure 1.. Correlation between blood HCQ levels and neonatal QTc.

(Panel A) Cord HCQ is plotted against QTc. (Panel B) Overall mean HCQ levels (obtained by averaging all HCQ levels throughout an individual pregnancy and cord blood level) are plotted against QTc. Subjects with an abnormally prolonged QTc are designated with red bold circles. All QTc intervals were calculated using the Bazett formula (QTcB).

Figure 2.

Box plots of maternal blood levels of HCQ during each trimester of pregnancy and delivery. M1T is baseline first trimester. M2T is second trimester. M3T is third trimester. M-Delivery is at the time of delivery. Median levels of HCQ (interquartile range) for M1T: 669 ng/mL (363–941); M2T: 877 ng/mL (604–1212); M3T: 849 ng/mL (652–1000); M-Delivery: 815 ng/mL (645–1080). Mean values denoted by + in box plot.

Figure 3.

Box plots of QTc interval data for subjects in first and fourth quartiles of cord blood HCQ levels and average HCQ levels during pregnancy. (Panel A) Comparison of QTc between the first and fourth quartiles of HCQ cord blood levels. Median QTc (interquartile range) in first HCQ quartile: 417 msec (390–424); in fourth HCQ quartile: 419 msec (404–436). (Panel B) Comparison of QTc between the first and fourth quartiles of HCQ levels averaged over pregnancy and cord blood. Median QTc (interquartile range) in first HCQ quartile: 413 msec (398, 443); in fourth HCQ quartile: 433 msec (407, 455). Mean values denoted by + in box plots. All QTc intervals were calculated using the Bazett formula (QTcB).