Is Hydroxychloroquine Safe During Pregnancy? Observations from Penn Medicine

Count: 5 Figures: 1 Submitted Manuscript Date: March 29, 2020 Corresponding Author: Mary Regina Boland, PhD Assistant Professor of Informatics Perelman School of Medicine University of Pennsylvania 423 Guardian Drive, 421 Blockley Hall Philadelphia, PA 19104 Email: [email protected] All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted May 6, 2020. ; https://doi.org/10.1101/2020.04.29.20085621doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. A novel strain of coronavirus appeared in December 2019. Over the next few months, this novel coronavirus spread throughout the world, being declared a pandemic by the World Health O rganization on March 11, 2020. As of this writing (March 28, 2020) over one hundred thousand individual s in the United States of America were confirmed cases. One way of treating the associated disease, COVID -19, is to reuse existing FDA - approved medications. One medication that has shown promise is hydroxychloroquine (HCQ). However, the utility and safety of HCQ among pregnant COVID-19 patients remains a concern. A recent open -label non -randomized clinical trial of HCQ and azithromycin as treatment for COVID-19 excluded pregnant and breastfeeding patients from the study [1]. HCQ is considered a Category C medication , indicating that it remains unknown what effect the drug will have on the fetus. There is evidence that HCQ may be safe during pregnancy, with previous research finding no increased risk of, prematurity, fetal death, retinopathy, low birth weight, stillbirth, or congenital defects[2-4]. However, there is also evidence that HCQ could result in fe tal harm with a recent meta-analysis finding an association between HCQ use and spontaneous abortion 3 and small for gestational age [5]. Therefore, clinicians may be faced with the difficult decision of deciding whether to treat their pregnant COVID-19 patients with HCQ. At Penn Medicine, we have pregnancy outcomes following 63,334 deliveries between 2010 and 2017 with the following outcomes annotated: Caesarean section delivery, preterm birth, multiple birth (e.g., twins, triplets) and stillbirth. We assessed whether there was an increased risk of any of these four outcomes followin g exposure to HCQ during pregnancy where exposure was determined to occur between 280 days (i.e., 40 weeks) and up to 1 day prior to the date of delivery. The Institutional Review Board at the University of Pennsylvania approved this study. We found that 28 deliveries had documented HCQ exposure , results shown in Figure. We did not find increased risk for any of the four measured outcomes (p>0.05): Caesarean Section, Preterm birth, Multiple birth, and Stillbirth. We also expanded our search to include all quine drugs (i.e., HCQ, primaquine, mefloquine, chloroquine phosphate) and found the same negative result (i.e., no increased risk). Our findings coupled with some of those in the literature[2-4] suggest that HCQ may not adversely a ffect fetal outcomes when taking HCQ during pregnancy. Therefore, clinicians may consider including pregnant patients with COVID-19 in clinical trials of HCQ when warranted. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted May 6, 2020. ; https://doi.org/10.1101/2020.04.29.20085621doi: medRxiv preprint CONFLICTS OF INTEREST The authors report no conflicts of interest. FUNDING This work was funded by the generous support of the University of Pennsylvania, Perelman School of Medicine. IRB APPROVAL #828000

[1] Gautret P, Lagier J-C, Parola P, Meddeb L, Mailhe M, Doudier B, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020:105949. [2] Kaplan YC, Ozsarfati J, Nickel C, Koren G. Reproductive outcomes following hydroxychloroquine use for autoimmune diseases: a systematic review and meta‐analysis. British journal of clinical pharmacology. 2016;81:835-48. [3] Cooper WO, Cheetham TC, Li DK, Stein CM, Callahan ST, Morgan TM, et al. Brief report: Risk of adverse fetal outcomes associated with immunosuppressive medications for chronic immune‐mediated diseases in pregnancy. Arthritis & Rheumatology. 2014;66:444-50. [4] Sperber K, Hom C, Chao CP, Shapiro D, Ash J. Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases. Pediatric Rheumatology. 2009;7:9. [5] Howren A, Rebić N, Sayre E, Tsao N, Amiri N, Baldwin C, et al. Perinatal exposure to conventional synthetic disease-modifying anti-rheumatic drugs in women with rheumatic disease and neonatal outcomes: a population-based study. Clinical and experimental rheumatology. 2020.   All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted May 6, 2020. ; https://doi.org/10.1101/2020.04.29.20085621doi: medRxiv preprint Figure. Hydroxychloroquine Exposure and Four Delivery Outcomes (Caesarean Section, Preterm Birth, Multiple Birth, Stillbirth) Using PennMedicine Data from 28 Pregnancies   All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted May 6, 2020. ; https://doi.org/10.1101/2020.04.29.20085621doi: medRxiv preprint