Sex- and Gender-specific Risk Factors of Post-COVID-19 Syndrome: A Population-based Cohort Study in Switzerland

BackgroundEvidence to date indicates that mortality of acute coronavirus disease (COVID-19) is higher in men than in women. Conversely, women seem more likely to suffer from long-term consequences of the disease and pronounced negative social and economic impacts. Sex- and gender specific risk factors of COVID-19-related long-term effects are unknown. MethodsWe conducted a multicentre prospective observational cohort study of 5838 (44.6% women) individuals in Switzerland who were tested positive for SARS-CoV-2 RNA between February and December 2020. Of all surviving individuals who met the inclusion criteria, 2799 (1285 [45.9%] women) completed a follow-up questionnaire. FindingsAfter a mean follow-up time of 197{+/-}77 days, women more often reported at least one persistent symptom (43.0% vs 31.5%, p<0.001) with reduced exercise tolerance and reduced resilience being the most frequently reported symptom in both sexes. Critical illness (intermediate or intensive care unit admission) during acute SARS-CoV-2 infection (odds ratio[95%CI]: 4.00[2.66-6.02], p<0.0001 was a risk factor of post-COVID syndrome in both women and men. Women with pre-existing mental illness (1.81[1.00-3.26], p=0.049), cardiovascular risk factors (1.39[1.03-1.89], p=0.033), higher self-reported domestic stress levels (1.15[1.08-1.22], p<0.0001), and feminine gender identity (1.12[1.02-1.24], p=0.02) increased the odds of experiencing post-COVID syndrome. Conversely, obesity (1.44[1.03-2.02], p=0.034) increased the odds of post-COVID syndrome in men, but not in women. Being responsible for household work (men, OR 0.82[0.69-0.97], p=0.021), taking care of children/relatives (women, 0.90[0.84-0.96], p=0.002) or being pregnant at the time of acute COVID-19 illness (OR 0.48[0.23-1.01], p=0.054) was associated with lower odds of post-COVID syndrome. InterpretationPredictors of post-COVID syndrome differ between men and women. Our data reinforce the importance to include sex and gender to identify patients at risk for post-COVID syndrome so that access to care and early intervention can be tailored to their different needs. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe performed a PubMed search for studies investigating short- and long-term health sequelae in COVID-19 survivors. We included all studies published prior to May 30th, 2021. The search comprised the following terms: (COVID-19 OR SARS-CoV-2 OR Coronavirus disease 2019 OR 2019-nCoV) AND (post COVID OR long COVID OR survivor OR recover OR persistent OR follow up OR discharge OR long-term OR sequelae). Previous studies have reported a variety of symptoms in COVID-19 survivors from different countries such as China (Wuhan), the UK, and the U.S. Overall, these studies showed that a substantial burden of health issues spanning multiple organ systems is experienced by patients who survive after the acute phase of COVID-19. The most frequent symptoms reported after acute infection were fatigue, muscle weakness, sleep disturbances, headache, dyspnoea, anxiety, depression, and anosmia. Two studies indicate that women are overrepresented amongst post-COVID-19 syndrome patients suffering from fatigue, headache, dyspnoea, or anosmia. However, the representativeness of the studies and the explicitness of provided information were insufficient due to lacking variables and/or small numbers of cases and the short duration of follow-up. Sex-and gender-specific predictors of post-COVID-19 syndrome are currently unknown. Added value of this studyIn a large cohort study (n=2799) with long follow-up (mean follow-up 197{+/-}77 days), we investigated sex- and gender-specific predictors of post-COVID-19 health sequalae. Our data allow for identification of sex- and gender-specific predictors of post-COVID-19 syndrome. In a multivariable association model, post-COVID-19 syndrome was associated with severity of illness and number of symptoms during acute SARS-CoV-2 infection in both sexes, while pre-existing mental illness and cardiovascular risk factors were significant predictors only in women. Conversely, obesity was independently associated with post-COVID-19 syndrome in men, but not in women. Gender-related risk factors of post-COVID syndrome were feminine traits and higher amount of domestic stress, both increasing the odds of post-COVID-19 syndrome in women, while pregnancy during acute COVID-19 illness and responsibility for childcare protected women, and responsibility for household work protected men from experiencing post-COVID-19 syndrome. Implications of all the available evidenceEvidence indicates that mortality from COVID-19 infection is higher in men than women. We provide evidence that female sex and gender is associated with long-term sequalae of COVID-19. Our data reinforce the importance of including gender to identify patients at risk for post-COVID-19 syndrome so that the functional return of both male and female COVID-19 survivors can be maximized.