The "sex gap" in COVID-19 trials: a scoping review

Schiffer, Veronique M.M.M.; Janssen, Emma B.N.J.; van Bussel, Bas C.T.; Jorissen, Laura L.M.; Tas, Jeanette; Sels, Jan-Willem E.M.; Bergmans, Dennis C.J.J; Dinh, Trang H.T.; van Kuijk, Sander M.J.; Hana, Anisa; Mehagnoul-Schipper, Jannet; Scheeren, Clarissa I.E.; Mesotten, Dieter; Stessel, Bjorn; Marx, Gernot; Hof, Arnoud W.J.van ´t; Spaanderman, Marc E.A.; van Mook, Walther N.K.A.; van der Horst, Iwan C.C.; Ghossein-Doha, Chahinda

BACKGROUND: Many studies investigate the role of pharmacological treatments on disease course in Corona Virus Disease 2019 (COVID-19). Sex disparities in genetics, immunological responses, and hormonal mechanisms may underlie the substantially higher fatality rates reported in male COVID-19 patients. To optimise care for COVID-19 patients, prophylactic and therapeutic studies should include sex-specific design and analyses. Therefore, in this scoping review, we investigated whether studies on pharmacological treatment in COVID-19 were performed based on a priori sex-specific design or post-hoc sex-specific analyses. METHODS: We systematically searched PubMed, EMBASE, UpToDate, clinical trial.org, and MedRxiv for studies on pharmacological treatment for COVID-19 until June 6th, 2020. We included case series, randomized controlled trials, and observational studies in humans (≥18 years) investigating antiviral, antimalarial, and immune system modulating drugs. Data were collected on 1) the proportion of included females, 2) whether sex stratification was performed (a priori by design or post-hoc), and 3) whether effect modification by sex was investigated. FINDINGS: 30 studies were eligible for inclusion, investigating remdesivir (n = 2), lopinavir/ritonavir (n = 5), favipiravir (n = 1), umifenovir (n = 1), hydroxychloroquine/chloroquine (n = 8), convalescent plasma (n = 6), interleukin-6 (IL-6) pathway inhibitors (n = 5), interleukin-1 (IL-1) pathway inhibitors (n = 1) and corticosteroids (n = 3). Only one study stratified its data based on sex in a post-hoc analysis, whereas none did a priori by design. None of the studies investigated effect modification by sex. A quarter of the studies included twice as many males as females. INTERPRETATION: Analyses assessing potential interference of sex with (side-)effects of pharmacological therapy for COVID-19 are rarely reported. Considering sex differences in case-fatality rates and genetic, immunological, and hormonal mechanisms, studies should include sex-specific analyses in their design to optimise COVID-19 care. FUNDING: None