Use of hydroxychloroquine during pregnancy and breastfeeding: An update for the recent coronavirus pandemic (COVID-19)

Motherisk Int J 2020;1:9

 

Yusuf Cem Kaplan MD (1), Gideon Koren MD (2, 3)

Terafar - Izmir Katip Celebi University Teratology Information Center, Turkey (1) and Adelson Faculty of Medicine, Ariel University(2), Motherisk Israel Program (3)

 

Question:
Recent in vitro studies and preliminary clinical trial data documented  the antiviral effect of chloroquine and hydroxychloroquine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)(1-4). Both drugs are becoming increasingly suggested by different national coronavirus disease 2019 (COVID-19) treatment guidelines (1-4). Is it safe to use hydroxychloroquine during pregnancy and lactation?

 

Answer:
The fetal safety of chloroquine has been documented in numerous studies and a recent meta analysis, justifying its use in pregnant women who have contracted the SARS-CoV-2 coronavirus

 

Hydroxychloroquine (HCQ) is a hydroxyl derivative of chloroquine, which is a widely used anti-malarial drug, with a more favorable clinical safety profile than other antimalarial drugs. The main indications of HCQ are rheumatoid arthritis, discoid and systemic lupus erythematosus and the suppressive treatment of malaria and acute malarial attacks (5). The mechanism of action in these diseases is thought to be through its immunomodulatory effect as a result of its complex interaction with  several steps in immune response such as the inhibition of lysosomal acidification, phagocytosis, proteolysis, antigen presentation and chemotaxis and decreasing the production of pro-inflammatory cytokines (6). In recent in-vitro studies, HCQ appears to inhibit SARS-CoV-2 viral replication and has the potential to interfere with other virus host interactions such as its fusion with the cell membrane, post-translational modification and viral release (1, 2).  Since the outbreak of this virus in China scientists have found in multicenter clinical trials that treating  patients diagnosed with this novel coronavirus pneumonia with chloroquine  shortened hospital stay and improve patient outcome.  (3-4).

As this is a clinically available drug, it is likely that in many cases of pregnant women contracting the virus, the issue of fetal safety of chloroquine  will  emerge. The objective of this review is to summarize existing data to help clinicians in their decisions.

 

Pregnancy

The ototoxic and retinotoxic findings in infants who were exposed to chloroquine in utero and similar findings in some animal studies raised some concerns about the safety of chloroquine and HCQ use during pregnancy (7-9). A case series reported some adverse electroretinogram findings for HCQ exposure (10). However these findings were questioned (11) and not confirmed by other case series (12-14). To date, the safety of HCQ use in pregnancy was reported in several observational cohort studies (15-21) and one randomized controlled trial (22).  A meta-analysis which was conducted in 2009 involving four of these studies found no increase in risk of major congenital malformations, spontaneous abortions, fetal death or prematurity (23).

The most recent systematic review and meta-analysis regarding HCQ use during pregnancy was conducted by our team  in 2016 (6). We pooled the data from all the studies mentioned above, seven observational cohorts and one randomized-controlled trial, totaling 740 HCQ-exposed infants and 1130 unexposed controls. The reported HCQ dose was 200-400 mg/day and duration of use varied from 3 months before and throughout pregnancy. The mothers also reported the use of other medications, some of which were corticosteroids, NSAIDs and azathioprine. We detected no significant increased risk of major malformations in general, as well as craniofacial, cardiovascular, nervous system and genitourinary malformations in infants who were exposed to HCQ in utero. Additionally, no significant increase in the rates of stillbirth, low birth weight and prematurity were detected. However, we detected a significant increase in rate of spontaneous abortion in the HCQ-exposed women, which may be associated with the underlying disease, was  (4).  A comprehensive review by the European League Against Rheumatism (EULAR) has also classified HCQ among the compatible drugs during pregnancy and recommended its continuation for maintenance of remission or the treatment of a disease flare during pregnancy (24).

 

Breastfeeding

Relative infant dose (RID) is the key parameter for evaluating the safety of medications during breastfeeding. It is calculated by dividing the dose offered to the infant via milk by the mother’s weight-adjusted dose. An RID of less than 10% of the mother’s weight-adjusted dose is generally considered safe for breastfeeding (25).

A review of the cases in LactMed which includes information regarding the concentrations of milk samples of more than 50 women who used HCQ during breastfeeding (100 to 400 mg/day) suggested a relative infant dose (RID) between 1.9 to 3.2% (26). This range is compatible with breastfeeding. However, in some of these cases much less RIDs were also reported, which may be because of inappropriate sample timing. An exception among these cases was one of the mothers who was taking 400 mg/day yielding an RID of 9.8%,. This mother was advised to discontinue  breastfeeding.

In addition,  similar analysis of LactMed reports (26), which included more than 60 breastfed infants (some of which were overlapping cases) whose mothers were using HCQ during breastfeeding provided no adverse effects on growth, development, motor skills and retinal findings. The duration of exposure of the infants through breast milk ranged between 1 to 86 months and the maternal dose varied between 200 to 400 mg/day.

 

Conclusions:

To date, the available evidence suggests no increase in risk of major congenital malformations following maternal HCQ use during pregnancy. For rheumatological diseases, the continuation of HCQ during pregnancy was recommended (24).  Available evidence regarding lactation also suggests that HCQ is compatible with breastfeeding (24). Putting this knowledge into the perspective of the recent corona pandemic suggests that, HCQ can be used for the treatment of COVID-19 infection, in usual rheumatological doses (200-400 mg/day) if clinically indicated. Although the dose of HCQ in the recent clinical trials (25) for the treatment of COVID-19 is in this range (400 mg/day), doses higher than 400 mg/day during pregnancy may necessitate an individual risk-benefit assessment. In addition, because milk concentrations are dose-dependent, doses over 400 mg/day may necessitate breastmilk sampling to ensure the RID stays in the acceptable ranges (less than 10%) with closer monitoring of the infant, accordingly.

 

References

1.    Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [published online ahead of print, 2020 Mar 9]. Clin Infect Dis. 2020;ciaa237. doi:10.1093/cid/ciaa237

2.    Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? [published online ahead of print, 2020 Mar 11]. Int J Antimicrob Agents. 2020;105938.

3.    Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):185-188. doi: 10.3760/cma.j.issn.1001-0939.2020.03.009.

4.    Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73. doi: 10.5582/bst.2020.01047. Epub 2020 Feb 19.

5.    PLAQUENIL®  [product monograph]. Concordia Pharmaceuticals Inc; 2017. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf. Accessed 2020 Mar 21.

7.    Kaplan YC, Ozsarfati J, Nickel C, Koren G. Reproductive outcomes following hydroxychloroquine use for autoimmune diseases: a systematic review and meta-analysis. Br J Clin Pharmacol. 2016;81(5):835–848.

8.    Ullberg S, Lindquist NG, Sjostrand SE. Accumulation of chorioretinotoxic drugs in the foetal eye. Nature 1970; 227: 1257–8.

9.     Paufique L, Magnard P. Retinal degeneration in two children following preventive antimalarial treatment of the mother during pregnancy. Bull Soc Ophtalmol Fr 1969; 69: 466–7.

10. Hart CW, Naunton RF. The ototoxicity of chloroquine phosphate. Arch Otolaryngol 1964; 80: 407–12.

11. Renault F, Flores-Guevara R, Renaud C, Richard P, Vermersch AI, Gold F. Visual neurophysiological dysfunction in infants exposed to hydroxychloroquine in utero. Acta Paediatr 2009; 98: 1500–3.

12. Ingster-Moati I, Albuisson E. Visual neurophysiological dysfunction in infants exposed to hydroxychloroquine in utero. Acta Paediatr 2010; 99: 4; author reply 4–5.

13. Klinger G, Morad Y,Westall CA, Laskin C, Spitzer KA, Koren G, Ito S, Buncic RJ. Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases. Lancet 2001; 358: 813–4.

14. Costedoat-Chalumeau N, Amoura Z, Duhaut P, Huong DL, Sebbough D, Wechsler B, Vauthier D, Denjoy I, Lupoglazoff JM, Piette JC. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 2003; 48: 3207–11.

15. Cimaz R, Brucato A, Meregalli E, Muscará M, Sergi P. Electroretinograms of children born to mothers treated with hydroxychloroquine during pregnancy and breast-feeding: comment on the article by Costedoat-Chalumeau et al. Arthritis Rheum 2004; 50: 3056–7.

16. Buchanan NM, Toubi E, Khamashta MA, Lima F, Kerslake S, Hughes GR. Hydroxychloroquine and lupus pregnancy: review of a series of 36 cases. Ann Rheum Dis 1996; 55: 486–8.

17. Costedoat-Chalumeau N, Amoura Z, Duhaut P, Huong DL, Sebbough D, Wechsler B, Vauthier D, Denjoy I, Lupoglazoff JM, Piette JC. Safety of hydroxychloroquine in pregnant patients with con- nective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 2003; 48: 3207–11.

18. Frassi M, Biasini C, Taglieti M, Daneli E, Faden D, Lojacono A, Motta M, Gerosa M, Meroni PL, Doria A, Cimaz R, Muscara R, Brucato A, Tincani A. Hydroxychloroquine in pregnant patients with rheumatic disease: a case control observation of 76 treated pregnancies. Lupus 2004; 13: 755.

19. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006; 54: 3640–7.

20. Diav-Citrin O, Blyakhman S, Shechtman S, Ornoy A. Pregnancy outcome following in utero exposure to hydroxychloroquine: a prospective comparative observational study. Reprod Toxicol 2013; 39: 58–62.

21. Cooper WO,CheethamTC, Li DK,Stein CM,Callahan ST, Morgan TM, Shintani AK, Chen N, GriffinMR, RayWA. Brief report: Risk of adverse fetal outcomes associated with immunosuppressive medications for chronic immune-mediated diseases in pregnancy. Arthritis Rheum 2014; 66: 444–50.

22. Gayed M, Khamashta M, Culliford D, Leone F, Toescu V, Bruce I, GilesI, Lee-SuanT, McHughN,Akil M,Edwards CJ,GordonC. Longterm outcomes of children born to mothers with SLE exposed to hydroxychloroquine in pregnancy. Rheumatology 2014; 53: i55.

23. Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JL, Tura BR, Albu- Querque EM, Jesus NR. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus 2001; 10: 401–4.

24. Sperber K, Hom C, Chao CP, Shapiro D, Ash J. Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases. Pediatr Rheumatol Online J 2009; 7: 9.

25. Götestam Skorpen C et al.The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 2016;75:795–810. doi:10.1136/annrheumdis-2015-208840

26. Bennett PN. Use of the monographs on drugs. In: Bennett PN, editor. Drugs and human lactation. 2nd ed. London, UK: Elsevier; 1996. p. 70-3.

27. The LactMed® database. Hydroxychloroquine. Last Revision: February 17, 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK501150/.  Accessed 2020 Mar 21.

28. ClinicalTrials.gov. U.S. National Library of Medicine. Available from: https://clinicaltrials.gov/ct2/results?cond=Coronavirus&term=hydroxychloroquine&cntry=&state=&city=&dist= Accessed 2020 Mar 21.