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COVID-19 affects men and women differently. So why don’t clinical trials report gender data?

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

COVID-19 doesn’t strike the sexes equally. Globally, for every 10 COVID-19 intensive care unit admissions among women, there are 18 for men; for every 10 women who die of COVID-19, 15 men die. In the United States, a gender gap is emerging in vaccination rates, with women ahead of men by 6 percentage points, according to the Centers for Disease Control and Prevention. And rare adverse effects from the AstraZeneca vaccine appear to strike women more frequently, whereas those from the Pfizer-BioNTech and Moderna vaccines more often affect young men.

But out of 45 COVID-19 randomized controlled trials whose results were published by December 2020, only eight reported the impact of sex or gender, according to a paper published today in Nature Communications. Other recent data show even simple counts of cases and vaccinations are not broken down by sex and gender.

Senior author Sabine Oertelt-Prigione, a gender and health researcher at Radboud University Medical Center, was disheartened by her group’s findings. “I would have assumed that [sex] would be picked up in the trials, simply because it’s such an evident piece of the puzzle,” she says. Skipping that step is potentially dangerous in trials of drugs that may affect men and women differently, given their physiological differences, Oertelt-Prigione says. And it misses an opportunity to learn about the workings of the disease, adds Susan Phillips, an epidemiologist at Queen’s University who was not involved in the study.

Martin Landray of the University of Oxford finds the lack of attention to sex effects surprising, too. He led the United Kingdom’s Recovery trial, which found the anti-inflammatory drug tocilizumab reduces the risk of death from COVID-19 and did explore whether results differed by sex (though it found none worth reporting). “I just thought that’s what everybody did.” Phillips, however, notes that researchers have often skipped gender analyses in published clinical research for more than 30 years. “The problem remains,” she says. “And this makes the current paper important.”

Oertelt-Prigione’s team searched PubMed for all papers on COVID-19 published before December 15, 2020, excluding commentaries, observational trials, and other studies to identify 45 randomized controlled trials that tested potential treatments and vaccines. All trials in the study reported numbers of male and female participants. But only eight examined whether results differed among men and women, the team found.

Even the largest COVID-19 trials sometimes skipped analysis by sex. For example, the giant Pfizer-BioNTech and Moderna vaccine trials explored whether vaccine efficacy differed by sex, finding more than 90% efficacy for both men and women. But neither trial broke out adverse effects by sex, as United Nations University gender and health researcher Lavanya Vijayasingham and colleagues noted in a letter in The Lancet in March. Even if these data are not published in a scientific journal, they are still collected and monitored, but low numbers of serious adverse events may mean that significant sex differences have not been detected, says State University of New York Upstate Medical University’s Stephen Thomas, a lead investigator on the Pfizer vaccine trial.  

The new paper’s findings are consistent with other studies. A recent, smaller study of COVID-19 trials, published in EClinicalMedicine, found zero out of 30 trials explored whether results were affected by sex. And an April paper in BMJ Global Health that examined a broader range of COVID-19 papers, including observational studies, found only 14 out of 121 analyzed whether sex affected the results.

Sometimes there may be reasons not to report sex-disaggregated data. The Landray team’s study of tocilizumab found one statistically significant sex difference: In patients who weren’t already on mechanical ventilation at the start of the trial, tocilizumab overall reduced the risk of either dying or needing mechanical ventilation—but analyzing by sex suggests the difference was only in men, not women. But for other outcomes, such as hospital discharge within a month, there was no statistically significant difference between the sexes. The team concluded it didn’t have “convincing evidence of there being a sex effect”—and thus didn’t report it in the paper, Landray says.

He notes that suggesting a sex difference where one might not exist can be harmful. For example, trials with small numbers of women suggested aspirin does not prevent heart attacks and strokes in women, but restricting the drug’s use based on such weak evidence would deprive women of a potentially beneficial drug, Landray argues.

At the moment, it’s up to individual investigators to bring sex and gender into their analyses, says Emily Smith, an epidemiologist at George Washington University. But “maybe some system-level interventions could help address it,” she says. If funding agencies or trial registries required sex-disaggregated reporting, that could motivate researchers to bake it into their trials.

The lack of data extends beyond clinical trials: Of 198 countries in the most recent monthly report from the Sex, Gender and COVID-19 Project database run by the nonprofit Global Health 50/50, only 37% report sex-disaggregated death data, and only 18% report sex-disaggregated vaccination data. Only Austria and two states in India have reported data for nonbinary people, according to the report, although some U.S. states also record nonbinary or transgender identities.

The COVID-19 pandemic has “shone a light on the importance of sex and gender in a way that very few other conditions have managed to do,” says Sarah Hawkes, co-director of Global Health 50/50. She and others say it’s time researchers shed their own light on those differences.