key: cord-0941107-mvbm030p
authors: Lampejo, Temi
title: Remdesivir for the treatment of COVID‐19 in pregnancy
date: 2021-04-14
journal: J Med Virol
DOI: 10.1002/jmv.26986
sha: 9d13b71a0ee17e6e7c1387d0a826977ba726f1b3
doc_id: 941107
cord_uid: mvbm030p

The devastating coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared by the World Health Organisation (WHO) in March 2020 and now at over 9 months since its declaration it continues to claim vast numbers of lives all over the world. There is no evidence that pregnant women are more susceptible to SARS-CoV-2 infection than the general population, however, pregnancy-associated immunological changes could potentially render pregnant individuals more vulnerable to severe COVID-19. This article is protected by copyright. All rights reserved.

The devastating coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared by the World Health Organisation (WHO) in March 2020 and now at over 9 months since its declaration, it continues to claim vast numbers of lives all over the world. 1 There is no evidence that pregnant women are more susceptible to SARS-CoV-2 infection than the general population; however, pregnancy-associated immunological changes could potentially render pregnant individuals more vulnerable to severe COVID-19 as has been previously observed with influenza A/H1N1, severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS). 2 Evidence from the United States (US) cohort study suggests that severe COVID-19 in pregnancy (predominantly in the third trimester) is associated with iatrogenic-associated preterm birth (75% delivered preterm). 3 Data from the UK cohort study of 427 pregnant women hospitalised with COVID-19 estimated an incidence of admission to hospital with confirmed SARS-CoV-2 infection of 4.9 per 1000 maternities. 2 In this study, 81% were in the third trimester or peripartum also suggesting that severe illness may be more common later in pregnancy. Ten percent (41/427) needed Level 3 critical care, of whom 80% (33/41) delivered their child while admitted with COVID-19 (66% delivered due to worsening respiratory condition). Overall mortality in pregnant women admitted with confirmed SARS-CoV-2 infection was 1.2% (5/427; three of whom died directly from complications of COVID-19). COVID-19 is responsible for a significant disease burden among pregnant women and although this may not be in excess of that observed in the general population, potential treatment options are limited even further in pregnant women, in part through their exclusion (often for justifiable reasons) from clinical trials. A review of COVID-19 treatment studies (of nonbiological drugs) at two specific time points (April 7-20, 2020 and July 10-15, 2020) found that pregnant women were excluded from 80% and 75% of studies during the first and second time points, respectively. 4

Remdesivir (GS-5734), an inhibitor of the viral RNA-dependent RNA polymerase was identified as a potential candidate for the treatment of COVID-19 after it was demonstrated to inhibit SARS-CoV-2 replication in vitro. 5, 6 In a large multicentre, international double-blind, randomised, placebo-controlled trial of 1062 patients with COVID-19 with evidence of lower respiratory tract infection, intravenous remdesivir (for 10 days or until hospital discharge or death) was associated with a shortened time to recovery when compared with placebo (median recovery time of 10 days with remdesivir vs. 15 days with placebo, p < 0.001) and remdesivir was also associated with a shortened time to discharge from hospital. 6 All-cause mortality was 11.4% with remdesivir and 15.2% with placebo. Adverse events occurred in 24.6% of the remdesivir group and 31.6% of the placebo group. This study excluded pregnant and breast-feeding women. A recent systematic review of remdesivir in hospitalised COVID-19 patients found that remdesivir significantly increased the recovery rate (by 22% and 14% on Days 7 and 28, respectively) compared to the control group, and significantly reduced 14-day mortality (by 36%) among moderate and severe COVID-19 patients but there was no significant difference in 28-day mortality. 7 Remdesivir has been the first drug to be approved by the Food and Drug Administration (FDA) in the United States (Emergency Use Authorisation was first granted on May 1, 2020) for use in children and adults hospitalised with COVID-19 and has also been approved in several other parts of the world. Pregnant women, however, are excluded from many recommendations for the use of remdesivir in COVID-19 largely due to a lack of clinical trial data. Its administration in pregnancy has primarily been on a compassionate use basis.

Safety data from the manufacturer report that at clinically relevant doses of remdesivir, no reproductive developmental toxicity was observed in animals (Remdesivir Investigator's Brochure, Gilead Sciences). Human data for the use of this agent in pregnant women with COVID-19 are extremely limited. In an earlier study of remdesivir in the treatment of Ebola virus disease, six pregnant women were assigned to receive remdesivir and there were no significant foetal/newborn, pregnancy, or maternal adverse events reported in any of the members of this subgroup. 8 Additionally, remdesivir has been used in the treatment of congenital Ebola virus infection in a neonate born to an Ebola virus-positive woman; the neonate tolerated the 12-day course of remdesivir well with no evidence of drug toxicity and at 12-month follow-up the child remained well. 9 The largest data for remdesivir in pregnant women with COVID-19 come from a US study by Burwick et al. in which 67 hospitalised pregnant patients (82% were ≥24 weeks gestation) with COVID-19

were treated on a compassionate use basis with remdesivir (and no other specific investigational therapies for COVID-19 were administered to these patients). 10 Ninety-three percent recovered from their illness despite 67% requiring intensive care unit (ICU) admission.

Remdesivir was generally well tolerated; incidence of serious adverse events was 18% (33% experienced an adverse event) and the majority of adverse events were deemed to be related to pregnancy and/or underlying disease. The study did not include a control group, the inclusion of which may have aided in addressing any uncertainties regarding whether similar adverse events rates would be observed in this patient population even in the absence of remdesivir administration. . There were no reports of mother-to-child SARS-CoV-2 transmission in any of the 13 cases. Table 1 summarises the published data for remdesivir in pregnancy-associated COVID-19 (studies that did not describe characteristics/outcomes/adverse events specifically for patients receiving remdesivir were not included).

The very limited data available to date do suggest overall that remdesivir is well tolerated in the latter stages (2nd/3rd trimesters) of pregnancy with a low risk of serious adverse events. There is an even greater paucity of data for its use in the first trimester of pregnancy. The anti-COVID-19 armamentarium for all pregnant patients is in dire need of urgent expansion and remdesivir could be a potentially instrumental member; however, further safety and efficacy data are required to support its use.

The peer review history for this article is available at https://publons. com/publon/10.1002/jmv.26986

The data that support the findings of this study are available from the corresponding author upon reasonable request. 

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