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Sex Differences in Long COVID

Shah DP 1 , Thaweethai T 2 , Karlson EW 3 , Bonilla H 4 , Horne BD 5 , Mullington JM 6 Show all authors , Wisnivesky JP 7 , Hornig M 8 , Shinnick DJ 2 , Klein JD 9 , Erdmann NB 10 , Brosnahan SB 11 , Lee-Iannotti JK 12 , Metz TD 13 , Maughan C 14 , Ofotokun I 15 , Reeder HT 2 , Stiles LE 14 , Shaukat A 11 , Hess R 16 , Ashktorab H 17 , Bartram L 7 , Bassett IV 18 , Becker JH 7 , Brim H 17 , Charney AW 7 , Chopra T 19 , Clifton RG 20 , Deeks SG 21 , Erlandson KM 22 , Fierer DS 7 , Flaherman VJ 23 , Fonseca V 24 , Gander JC 25 , Hodder SL 26 , Jacoby VL 21 , Kotini-Shah P 27 , Krishnan JA 27 , Kumar A 4 , Levy BD 3 , Lieberman D 28 , Lin JJ 7 , Martin JN 29 , McComsey GA 30 , Moukabary T 31 , Okumura MJ 21 , Peluso MJ 21 , Rosen CJ 32 , Saade G 33 , Shah PK 1 , Sherif ZA 17 , Taylor BS 1 , Tuttle KR 34 , Urdaneta AE 35 , Wallick JA 36 , Wiley Z 15 , Zhang D 37 , Horwitz LI 11 , Foulkes AS 2 , Singer NG 30 , RECOVER Consortium

Affiliations 

  • 1 Long School of Medicine, University of Texas Health Science Center, San Antonio
  • 2 Massachusetts General Hospital Biostatistics, Somerville
  • 3 Brigham and Women's Hospital, Boston, Massachusetts
  • 4 Division of Infectious Diseases, Department of Medicine, Stanford University, Palo Alto, California
  • 5 Intermountain Heart Institute, Intermountain Health, Salt Lake City, Utah
  • 6 Department of Medicine, Harvard Medical School, Boston, Massachusetts
  • 7 Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
  • 8 Columbia University Mailman School of Public Health, New York, New York
  • 9 Department of Pediatrics, Stanford University, Palo Alto, California
  • 10 Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham
  • 11 Department of Medicine, NYU Grossman School of Medicine, New York, New York
  • 12 Department of Neurology, University of Arizona College of Medicine, Phoenix
  • 13 Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City
  • 14 RECOVER Patient, Caregiver, or Community Representative, New York, New York
  • 15 Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
  • 16 Department of Population Health Sciences, Spencer Fox Eccles School of Medicine at the University of Utah, Salt Lake City
  • 17 Howard University College of Medicine, Washington, DC
  • 18 Department of Medicine, Massachusetts General Hospital, Boston
  • 19 Cedars-Sinai Medical Center, Los Angeles, California
  • 20 Department of Epidemiology, The George Washington University, Washington, DC
  • 21 Department of Medicine, University of California San Francisco
  • 22 Division of Infectious Diseases, Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora
  • 23 Department of Pediatrics, University of California San Francisco
  • 24 Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana
  • 25 Center for Research and Evaluation, Kaiser Permanente of Georgia, Atlanta
  • 26 Department of Medicine, West Virginia University, Morgantown
  • 27 Illinois Research Network, University of Illinois Chicago
  • 28 Banner Health, Tucson, Arizona
  • 29 Department of Epidemiology and Biostatistics, University of California San Francisco
  • 30 University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
  • 31 University of Arizona, Tucson
  • 32 MaineHealth Institute for Research, Scarborough
  • 33 Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston
  • 34 Providence Inland Northwest Health, Spokane, Washington
  • 35 Department of Emergency Medicine, Division of Emergency Critical Care, Stanford University, Palo Alto, California
  • 36 Swedish Health Services, Seattle, Washington
  • 37 Biological Sciences Division, University of Chicago, Chicago, Illinois
JAMA Netw Open, 2025 Jan 02;8(1):e2455430.
PMID: 39841477 DOI: 10.1001/jamanetworkopen.2024.55430

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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