Farname Inc. in collaboration with Iranian Society of Gynecology Oncology

Document Type : Review Article

Authors

1 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

2 Emergency Medicine Research Team, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a chief concern of the international community. As of May 2021, more than 150 million cases and 3.2 million deaths have been recorded. Considering the early struggle in treating COVID-19 patients, the researchers and clinicians have decided to try the previously available drugs according to their mechanisms of action. This article aims to review the potential drugs for COVID-19 patients during pregnancy and breastfeeding and their safety. PubMed and Scopus databases and Google Scholar engine were searched with the proper combination of the free keywords and MeSH Terms of COVID-19, SARS-CoV-2, Pregnancy, Breastfeeding, Treatment, Pharmacotherapy, Drug Therapy, and Drug Safety. All relevant clinical studies published until the end of 2020 were included in this review. Many antivirals, antibiotics, antiparasitics, and antipyretics have been proposed, but most of them are not registered for COVID-19 or have demonstrated little effect on the disease. Since there is still a long way to find an effective drug for the treatment of COVID-19, prevention is currently the most effective way. Also, prescribing drugs to these two groups of patients should be done according to the safety recommendations.

Keywords

Main Subjects

Introduction
 


On January 7th, 2020, the Chinese Center for Disease Control and Prevention (China CDC) identified a new coronavirus, later called the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by World He-alth Organization (WHO) (1). The virus rapidly spread globally and became a chief international concern, with more than 150 million confirmed cases and 3.2 million reported deaths until May 2021 (2). From the first days, clinicians and researchers worldwide attempted to find effective drugs to treat coronavirus disease 2019 (CO-VID-19), but no drug was approved as a definitive treatment. In this situation, left with no other choice than to use the formerly used drugs, most current clini-cal approaches consist of repurposing the previously available drugs that are expected to act as potential anti-COVID-19 agents, based on their underlying mechanisms of action.
Besides the general considerations regarding the drug-to-drug interactions, as the pregnant and infants are among the most vulnerable groups, and the beha-vior of the virus among pregnant women and infants is still ambiguous (3), we aim to review the safety of using the repurposed medications during the pregnancy and breastfeeding in this study.


 

 
Materials and Methods

During this review, PubMed and Scopus databases and Google Scholar engine were searched with the free keywords and MeSH Terms of COVID-19, SARS-CoV-2, Pregnancy, Breastfeeding, Treatment, Pharma-cotherapy, Drug Therapy, and Drug Safety, for articles published until the end of 2020. All relevant clinical studies were considered in this review.

 

Results & Discussion

The proposed medications for the treatment of COVID-19 infection in pregnant or breastfeeding patients are identified as below:
 
Antiparasitics
Chloroquine and Hydroxychloroquine are FDA-approved agents against malaria. The immunomo-dulatory effects and the impact of inhibiting the virus-cell fusion have turned these drugs into prodigious hopes for COVID-19 treatment (4). Although Chloro-quine and Hydroxychloroquine can pass through the placental barrier, studies have shown that no danger threatens the fetus (5). Despite the little excretion of Chloroquine into the milk, the American Academy of Pediatrics considers it compatible with breastfeeding, leaving no concern around the usage of Chloroquine and Hydroxychloroquine during breastfeeding (6). Recently, several studies, including the WHO Solidari-ty clinical trial, have reported that Chloroquine and Hy-droxychloroquine have low efficacy in treating COV-ID-19 patients, which has led to omitting these drugs from the COVID-19 treatment protocols in most of the countries (7).

Antibiotics
As a broad-spectrum antibiotic in respiratory infect-ions, Azithromycin is another drug that has been inves-tigated as a choice of pharmacotherapy for SARS-CoV-2 infection. With a history of proven antiviral act-ivty against Ebola, Zika, and Influenza A virus subtype H1N1, some researchers believe that comparing to Chloroquine and Hydroxychloroquine, Azithromycin could possibly be a better choice (8). Studies have shown that the combination therapy of Hydroxychloro-quine and Azithromycin was influential in the treat-ment of COVID-19 patients (9). Nevertheless, a recent systematic review of the literature found no efficacy for this drug in COVID-19 patients (10). Also, the results of COALITION I and II clinical trials in Brazil found no improvement in clinical outcomes of the 447 enrolled COVID-19 patients (11). Today, the Infect-ious Diseases Society of America (IDSA) guideline recommends against the combination therapy of Azith-romycin and Hydroxychloroquine because of reported increase in risk of QT prolongation, but this recomm-endation did not address the use of this drug against secondary bacterial pneumonia in COVID-19 patients (12). Azithromycin excretes into human milk, but there are limited data available in both human and animal studies regarding the harmful effects of Azithromycin on the fetus or infant. However, in case of clear need, Azithromycin can be used during pregnancy and breastfeeding (13).
Antivirals
A failed Ebola drug, Remdesivir, acts well in shortening the recovery time of COVID-19 patients. The FDA authorized this drug for emergency use on October 22nd, 2020. Although on November 20th, WHO recommended against Remdesivir (14), on November 25th, FDA declared that “The approval of Remdesivir for the treatment of patients hospitalized with COVID-19 met the legal and scientific standard” in a published statement (15). The safety of Remdesivir usage during pregnancy and breastfeeding is still under investing-ation. However, its usage during pregnancy is only all-owed after harm-benefit assessment for each patient. A case report of successful management of pregnant women in the third trimester with Remdesivir reco-mmended including pregnant women in clinical trials (16). Nevertheless, almost all clinical trials have excluded pregnant and breastfeeding women from their sample (17). The results of a study conducted on pregnant women who were treated with Remdesivir showed a high recovery rate with a low rate of serious adverse events (18). In this study, 93% of patients were recovered, and 90% were discharged, and the rate of serious adverse events was 16%. Only the severe cases of COVID-19 had the indication for Remdesivir injection. In this situation, it is most probably not to breastfeed their infants (19).
Lopinavir/Ritonavir as a licensed treatment for HIV had been recommended for COVID-19 treatment in many countries. Contrary to clinicians' hope, previous studies have shown no significant improvement in the clinical conditions of COVID-19 patients (7). While the previous studies have shown no concern regarding the standard-dose prescription of this drug during pregnancy, the use of the oral solution is contraind-icated during pregnancy, as it contains alcohol and propylene glycol (20). Most of the available guidelines recommend HIV-infected mothers not to breastfeed their infants, so there is limited data about this drug's safety during breastfeeding. Despite the little excretion in breastmilk, there is no report of adverse events caus-ed by using Lopinavir/Ritonavir in infants (21). Also, a recent systematic review has reported low placental transfer of Lopinavir/Ritonavir (22).
Favipiravir is another potential antiviral agent against COVID-19. Even though there are reports of its efficacy against mild and moderate cases of COVID-19, numerous contrary studies are available (23). A rec-ent systematic review has reported Favipiravir as an effective drug in improving the clinical condition of COVID-19 patients (24). Although Favipiravir has rec-eived approval for emergency use in many countries, further studies are still needed to substantiate the effective role of this drug (25). Thirty-one clinical trials have already been registered, which will provide more reliable evidence of using this drug against COVID-19. Favipiravir has shown teratogenic effects in several species and should not be prescribed for pregnant women (26). There is no information about its excre-tion into milk and safety for the newborn (21), but according to animal studies, breastfeeding is contrain-dicated during the treatment course of Favipiravir (26).
Another proposed agent for COVID-19 therapy is Interferon beta-1a (IFb1a), an immunomodulatory agent with antiviral effects used in the treatment of multiple sclerosis (MS). A clinical trial of 20 patients recommended adding IFb1a to the treatment regimen of infected patients (27). Also, a controlled trial of safety and efficacy of inhaled nebulized Interferon beta-1a found it effective in treating COVID-19 (28), in contrast with the results of the WHO Solidarity study (29). Notably, the pregnant and lactating women were excluded from the studies. Animal studies showed no teratogenic effects of IFb1a. Even though the usage of this agent during pregnancy was contraindicated, on April 4th, 2020, FDA approved that the drug does not have deleterious effects on pregnancy and pregnancy-related outcomes; however, most of the ongoing clinical trials excluded pregnant and lactating women from their study (30). Since the levels of interferon beta-1a excretion in human milk are negligible, no adverse infant effects had been reported in women who have breastfed while taking IFb1a (19).
Baricitinib
Baricitinib is a long-term medication against rheu-matoid arthritis, which has shown potential for CO-VID-19 treatment and received the FDA approval for emergency use combined with Remdesivir (31). This approval was primarily based on the results of a large randomized controlled trial of 1033 participants, which showed that compared with the Remdesivir mono-therapy, Remdesivir and Baricitinib has better efficacy in improving the clinical status of the COVID-19 patients (32). Although a recent case report stated the positive outcomes of using Baricitinib in the first 17 weeks of pregnancy (33), available clinical and exp-erimental studies recommend against prescribing Bari-citinib during pregnancy and breastfeeding.
Antipyretics

Fever is the most common symptom of COVID-19 (34). Defects of craniofacial devolvement, teeth, and heart problems are also commonly observed (35). Even mild exposure during the preimplantation period could result in abortion (36). In order to prevent the compli-cations of fever, Acetaminophen is a safe choice for the pregnant, but the use of Ibuprofen is a point of contro-versy. Studies claim that Ibuprofen may exacerbate the patients’ condition by increasing the amount of angiot-ensin-converting enzyme 2 (ACE2) (37).
On the other hand, studies claim to treat critically ill patients by blocking the inflammatory mediator interleukin-6 with this drug (38). Finally, on March 19th, the World Health Organization (WHO) stated that there is not enough evidence against the use of Ibuprofen, and they do not advise against it. Generally, pregnant women are recommended to avoid taking Ibuprofen, especially during the third trimester, since it could lead to premature closure of the fetal ductus arteriosus and develop heart problems in the fetus. Hence, physicians should weigh the benefits and harms before prescribing Ibuprofen. As a preferred choice of analgesic during lactation, the excretion of Ibuprofen into the breast milk is extremely low. It should be noted that NIH advises avoiding both Ibuprofen and Aceta-minophen during the first trimester of the pregnancy.

 

 

 
Conclusion

Prescribing medication for pregnant or lactating patients infected with SARS-CoV-2 is challenging. A summary of drug safety for pregnancy and lactation is presented in Table 1. The results of the solidarity clinical trial for COVID-19 treatments launched by WHO found little or no effect for Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon. More than mentioned drugs, novel ribonucleoside analog (NHC, EIDD-1931) was promising in recent studies. Preclinical studies found it a potential therapy against SARS-CoV-2, MERS-CoV, and SARS-CoV, but we still need clinical studies to confirm its safety and efficacy. It seems that there is still a long way to find an effective drug for the treatment of COVID-19; therefore, preventing infection is the most effective way to cross through this pandemic.

 Table 1. Safety categories of potential COVID-19 drugs during pregnancy and excreted into milk

Drug Australian Drug pregnancy Categories United States FDA pregnancy category Excretion into human milk
Acetaminophen A Not Assigned. Yes
Azithromycin B1 B Yes
Baricitinib D Not formally assigned. Yes2
Chloroquine A/D1 Not formally assigned. Small amounts
Favipiravir - - -
Hydroxychloroquine D Not formally assigned. -
Ibuprofen C C Small amounts
Interferon-beta-1a D C -
Lopinavir/Ritonavir B3 Not assigned. Yes
Remdesivir B2 Not assigned. Yes2

1For malaria treatment: D and for Malaria prophylaxis: A.2Based on animal studies.

 

Acknowledgments

 

None.

 

Ethical Permission

Not applicable.

 

Authors Contribution

Conceptualization, A.N., and MS.H.; data curation, A.N., and S.S.; writing—original draft preparation, A.N., and S.S; writing—review and editing, MS.H.; project administration, MS.H. All authors have read and agreed to the published version of the manuscript.
 

 
Conflicts of Interest

None declared by Authors.
 

 

Funding/ Supports

No funding was received for this research

 

1. Lancet T. Emerging understandings of 2019-nCoV. Lancet (London, England). 2020;395(10221):311. [DOI:10.1016/S0140-6736(20)30186-0]
2. WHO Coronavirus (COVID-19) Dashboard. Available from: https://covid19.who.int/.
3. Oliveira LV, Silva C, Lopes LP, Agra IKR. Current evidence of SARS-CoV-2 vertical transmission: an integrative review. Rev Assoc Med Bras (1992). 2020;66Suppl 2(Suppl 2):130-5. [DOI:10.1590/1806-9282.66.s2.130]
4. Monteiro WM, Brito-Sousa JD, Baía-da-Silva D, Melo GCd, Siqueira AM, Val F, et al. Driving forces for COVID-19 clinical trials using chloroquine: the need to choose the right research questions and outcomes. Revista da Sociedade Brasileira de Medicina Tropical. 2020;53. [DOI:10.1590/0037-8682-0155-2020]
5. Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology. 2015;23(5):231-69. [DOI:10.1007/s10787-015-0239-y]
6. Drugs Co. The transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108(3):776-89. [DOI:10.1542/peds.108.3.776]
7. Consortium WHOST, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2021;384(6):497-511. [DOI:10.1056/NEJMoa2023184]
8. Bleyzac N, Goutelle S, Bourguignon L, Tod M. Azithromycin for COVID-19: More Than Just an Antimicrobial? : Springer; 2020. [DOI:10.1007/s40261-020-00933-3]
9. 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. [DOI:10.1016/j.ijantimicag.2020.105949]
10. Abubakar AR, Sani IH, Godman B, Kumar S, Islam S, Jahan I, et al. Systematic Review on the Therapeutic Options for COVID-19: Clinical Evidence of Drug Efficacy and Implications. Infect Drug Resist. 2020;13:4673-95. [DOI:10.2147/IDR.S289037]
11. Furtado RHM, Berwanger O, Fonseca HA, Correa TD, Ferraz LR, Lapa MG, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020;396(10256):959-67. [DOI:10.1016/S0140-6736(20)31862-6]
12. Published by IDSA on 4/11/2020. Last updated. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19.
13. Keskin-Arslan E, Kaplan YC, Koren G. Use of azithromycin during pregnancy and breastfeeding: A coronavirus pan-demic (COVID-19) update. 2020.
14. WHO. WHO recommends against the use of remdesivir in COVID-19 patients. 20 November 2020.
15. fda. Remdesivir (Veklury) Approval for the Treatment of COVID-19-The Evidence for Safety and Efficacy. 11/25/2020.
16. Maldarelli GA, Savage M, Mazur S, Oxford-Horrey C, Salvatore M, Marks KM. Remdesivir Treatment for Severe COVID-19 in Third-Trimester Pregnancy: Case Report and Management Discussion. Open Forum Infect Dis. 2020;7(9):ofaa345. [DOI:10.1093/ofid/ofaa345]
17. Berghella V, Hughes B. Coronavirus disease 2019 (COVID-19): Pregnancy issues and antenatal care.
18. Burwick RM, Yawetz S, Stephenson KE, Collier AY, Sen P, Blackburn BG, et al. Compassionate Use of Remdesivir in Pregnant Women with Severe Covid-19. Clin Infect Dis. 2020.
19. Anderson PO. Antivirals for COVID-19 and Breastfeeding. Breastfeed Med. 2020;15(10):605-7. [DOI:10.1089/bfm.2020.0268]
20. Pasley MV, Martinez M, Hermes A, d'Amico R, Nilius A. Safety and efficacy of lopinavir/ritonavir during pregnancy: a systematic review. AIDS Rev. 2013;15(1):38-48.
21. Levonorgestrel I. Drugs and Lactation Database (LactMed)[Internet]. Bethesda (MD): National Library of Medicine (US). 2019:63-7.
22. Louchet M, Sibiude J, Peytavin G, Picone O, Treluyer JM, Mandelbrot L. Placental transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019. Am J Obstet Gynecol MFM. 2020;2(3):100159. [DOI:10.1016/j.ajogmf.2020.100159]
23. Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. MedRxiv. 2020. [DOI:10.1101/2020.03.17.20037432]
24. Wei FF, Moradkhani A, Hemmati Hezaveh H, Miraboutalebi SA, Salehi L. Evaluating the Treatment with Favipiravir in Patients Infected by COVID-19: A Systematic Review and Meta-analysis. International Journal of Scientific Research in Dental and Medical Sciences. 2020;2(3):87-91.
25. Agrawal U, Raju R, Udwadia ZF. Favipiravir: A new and emerging antiviral option in COVID-19. Med J Armed Forces India. 2020;76(4):370-6. [DOI:10.1016/j.mjafi.2020.08.004]
26. Hayden FG, Shindo N. Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis. 2019;32(2):176-86. [DOI:10.1097/QCO.0000000000000532]
27. Payandemehr P, Azhdarzadeh M, Bahrami-Motlagh H, Hadadi A, Najmeddin F, Shahmirzaei S, et al. Interferon beta-1a as a Candidate for COVID-19 Treatment; An Open-Label Single-Arm Clinical Trial. Advanced Journal of Emergency Medicine. 2020;4(2s):e51-e.
28. Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, Mankowski M, et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 2021;9(2):196-206. [DOI:10.1016/S2213-2600(20)30511-7]
29. Peiffer-Smadja N, Yazdanpanah Y. Nebulised interferon beta-1a for patients with COVID-19. Lancet Respir Med. 2021;9(2):122-3. [DOI:10.1016/S2213-2600(20)30523-3]
30. Bosi E, Bosi C, Rovere Querini P, Mancini N, Calori G, Ruggeri A, et al. Interferon beta-1a (IFNbeta-1a) in COVID-19 patients (INTERCOP): study protocol for a randomized controlled trial. Trials. 2020;21(1):939. [DOI:10.1186/s13063-020-04864-4]
31. FDA. Coronavirus (COVID-19) Update: FDA Authorizes Drug Combination for Treatment of COVID-19 2020 [Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-combination-treatment-covid-19.
32. Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021;384(9):795-807. [DOI:10.1056/NEJMoa2031994]
33. Costanzo G, Firinu D, Losa F, Deidda M, Barca MP, Del Giacco S. Baricitinib exposure during pregnancy in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2020;12:1759720X19899296. [DOI:10.1177/1759720X19899296]
34. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-9. [DOI:10.1001/jama.2020.1585]
35. Le Gouez A, Benachi A, Mercier FJ. Fever and pregnancy. Anaesth Crit Care Pain Med. 2016;35 Suppl 1:S5-S12. [DOI:10.1016/j.accpm.2016.06.007]
36. Edwards MJ. Review: Hyperthermia and fever during pregnancy. Birth Defects Res A Clin Mol Teratol. 2006;76(7):507-16. [DOI:10.1002/bdra.20277]
37. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet Respiratory Medicine. 2020;8(4):e21. [DOI:10.1016/S2213-2600(20)30116-8]
38. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. British Medical Journal Publishing Group; 2020. [DOI:10.1136/bmj.m1086]