Sex differences in Long COVID
Shah, DP; Thaweethai, T; Karlson, EW; et al.; RECOVER Consortium, JAMA Network Open
Published
January 2025
Journal
JAMA Network Open
Abstract
Importance: A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain. Objective: To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection. Design, setting, and participants: This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)-Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection. Exposure: Self-reported sex (male, female) assigned at birth. Main outcomes and measures: Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity. Results: Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants. Conclusions and relevance: In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.
Authors
Dimpy P Shah, Tanayott Thaweethai, Elizabeth W Karlson, Hector Bonilla, Benjamin D Horne, Janet M Mullington, Juan P Wisnivesky, Mady Hornig, Daniel J Shinnick, Jonathan D Klein, Nathaniel B Erdmann, Shari B Brosnahan, Joyce K Lee-Iannotti, Torri D Metz, Christine Maughan, Ighovwerha Ofotokun, Harrison T Reeder, Lauren E Stiles, Aasma Shaukat, Rachel Hess, Hassan Ashktorab, Logan Bartram, Ingrid V Bassett, Jacqueline H Becker, Hassan Brim, Alexander W Charney, Tananshi Chopra, Rebecca G Clifton, Steven G Deeks, Kristine M Erlandson, Daniel S Fierer, Valerie J Flaherman, Vivian Fonseca, Jennifer C Gander, Sally L Hodder, Vanessa L Jacoby, Pavitra Kotini-Shah, Jerry A Krishnan, Andre Kumar, Bruce D Levy, David Lieberman, Jenny J Lin, Jeffrey N Martin, Grace A McComsey, Talal Moukabary, Megumi J Okumura, Michael J Peluso, Clifford J Rosen, George Saade, Pankil K Shah, Zaki A Sherif, Barbara S Taylor, Katherine R Tuttle, Alfredo E Urdaneta, Julie A Wallick, Zanthia Wiley, David Zhang, Leora I Horwitz, Andrea S Foulkes, Nora G Singer; RECOVER Consortium
Keywords
Humans; Female; Male; COVID-19/epidemiology; Middle Aged; Adult; SARS-CoV-2; Sex Factors; United States/epidemiology; Post-Acute COVID-19 Syndrome; Cohort Studies; Aged; Risk Factors; Prospective Studies
Short Summary
This RECOVER study looks at whether a person’s sex at birth affects their risk of developing Long COVID. Researchers studied a large group of people with acute COVID-19, which is the early stage of the illness. They looked at factors like age, race, ethnicity, the COVID variant they had, and how severe their first infection was. They found that females were more likely to have Long COVID symptoms than males. Among females, the risk of getting Long COVID changed based on age, pregnancy status during a COVID infection, and if they had gone through menopause. Researchers discovered that the risk of getting Long COVID was higher in females ages 40–54 years and females who had not gone through menopause. On the other hand, females who already went through menopause were not at a higher risk compared to males. More research is needed to understand why differences in sex at birth may put someone at higher risk of experiencing the long-term effects of COVID. Knowing this and understanding which hormones play a role in Long COVID risk could help researchers develop treatments and ways to prevent Long COVID that focus on sex at birth.