Recognising the importance of sex and gender

In line with the SAGER guidelines, we first examined title, abstract and introduction. Among five single sex studies, four observational studies were on pregnancy as indicated in the title and abstract. One article focused on young males and highlighted the single-sex nature of the study in the title but did not justify the exclusion of women. Although sex and gender differences of COVID-19 have been reported, none of the clinical trials and only four observational studies (6%) reflected this in their introductions (table 1).

Under-representation of women in clinical research

The SAGER guidelines recommend reporting how sex and gender were considered in the study design and encourages gender balance, or a justification for exclusion of one gender. None of the interventional or observational studies mentioned how sex or gender were considered in recruitment strategies or justified differing rates of women and men.

Overall, the mean proportion of women in our studies was 43% (figure 1). Only 31% of the studies were gender balanced, defined as 45%–55% female participation. A majority of studies (57%) reported lower than 45% women. A small proportion of studies (12%) had an over representation of women (>55%). There was no significant difference observed between interventional and observational studies (p=0.693), nor between large (>median; n=102 and n=154 for observational and interventional studies, respectively) and small studies (p=0.436). Vaccine studies were more likely than treatment trials (p=0.038) to have better gender balance.

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Figure 1

Female participation by study type and intervention type.

None of the studies justified under-representation or over-representation of women. In observational studies, most of which recruited participants in hospital settings, the over-representation of men may reflect the corresponding higher rate of hospitalisation among men. In clinical trials, where recruitment and sampling strategies are designed by researchers, women’s under-representation suggests gender-related barriers to women’s participation, or a lack of attention by the researchers to equal recruitment into the study.

We noted that pregnant women were ineligible for all the interventional trials in our sample and only included in four observational studies. This represents a persistent trend where pregnant women are excluded from clinical studies. However, such exclusion puts women and the fetus at greater risk as they may not benefit from treatment and vaccination due to insufficient data on safety and efficacy during pregnancy.8 9

Data disaggregation by sex and gender analysis

The SAGER guidelines advise that outcome data and data on participant withdrawals should be routinely disaggregated by sex, and that sex-based and gender-based analyses should be reported regardless of positive or negative outcome.

Out of 121 studies that were eligible to both women and men, only eight studies (7%) (seven observational and one interventional) disaggregated their main outcome data by sex. Only four observational studies disaggregated their main outcome data by age and sex concurrently.

Of 14 interventional trials that reported participant discontinuations, none provided the data by sex. While this may be due to small number of dropouts, this trend renders it difficult to investigate possible sex-related or gender-related reasons for discontinuation, such as greater or more serious adverse effects or the inconvenience of participating in the study.

A majority (89%) of studies did not mention whether or not sex or gender differences were analysed or observed. Only 14 studies (11%) (12 observational and two interventional trials) included an analysis of sex differences in their results. All of these studies noted a difference between women and men, either in the differing numbers of women and men in the hospital settings, or whether being female or male were associated with differing disease outcomes. One clinical trial noted different responses between women and men to a vaccination. While the numbers were low, observational studies were more likely than interventional trials to include sex or gender in their results sections (p=0.022). In studies that identified differences between women and men, there was an inadequate analysis of the underlying mechanism, and generally, there was a lack of analysis of gender-related factors in the studies, despite gender being an influential factor on risk, exposure and outcome.

While studies may not be sufficiently powered to allow meaningful subgroup analysis, the SAGER guidelines recommend integration of these dimensions at the onset and in the design of the studies to enable meaningful analysis. Regardless, making outcome data available disaggregated by sex is important to allow systematic reviews and meta-analyses, or reveal trends that merit further investigation.

A renewed rationale for the SAGER guidelines

Our analysis confirms previous reports that have revealed inadequate reporting of sex disaggregated data and gender analysis in academic publications. In 2016, Avery and Clark examined 54 clinical trials published in prestigious medical journals and noted a similar level (41%) of female participation. While they noted a higher share (48%) of trials reporting sex-related analyses than our analysis, they noted that only 5% of the trials discussed any sex differences in the discussion section. A more recent article on cardiovascular interventional trials report that among articles published in 2017, only 23.5% included sex-specific efficacy endpoints and 8.6% sex-specific safety outcomes. This represents a decline since 2010 when the corresponding figures were 34.4% and 11.1%, respectively.10 In a recent systematic review by Brady et al of COVID-19 registered studies, only 4.1% mention sex and/or gender in the analysis, with only ‘20 of the 1381 interventional trials planning to consider sex as a variable upon analysis’.11 This analysis confirms the persistent lack of consideration for sex and gender at the planning stages of clinical trials on COVID-19 and in reporting. A recent report of the adverse effects following the administration of the Pfizer-BioNTech COVID-19 Vaccine in the USA reveals that more than 90% of anaphylaxis and non-anaphylaxis allergic reactions occurred in women, illustrating the importance of capturing these trends during clinical trials.12 Similar trends have been reported following the administration of the Moderna vaccine.

The low levels of adherence to the SAGER guidelines are in stark contrast to commitments to the SAGER guidelines and gender sensitive reporting by some leading journals, such as The British Medical Journal Global Health, The Lancet and The Journal of the American Medical Association. The gender blind reporting is particularly worrisome in the context of COVID-19, when scientific articles are being produced in an unprecedented volume and speed and risk generating biased and incomplete evidence that can hamper more tailored and effective response.11 13–15

These results are disappointing given the growing number of recent efforts to address the gender data gap in research and reporting practices. The SAGER guidelines were developed in 2016 as a tool for researchers, reviewers and editors to address the gender bias in research and reporting.6 Editors can play an important role encouraging researchers to conduct exploratory subgroup analysis ‘in response to reviewer and editorial comments’, to make sex disaggregated data available16 and to integrate sex and gender dimentions in to future reserach design.16

The SAGER guidelines have been widely cited, endorsed and adopted by publishers, such as Springer and Elsevier and an increasing number of journals, including those that have published some of the COVID-19 clinical trials in this systematic review.17 18 However, these commitments have not yet translated into systematic implementation or routine requirements by journals. By implementing the SAGER guidelines, editors could be instrumental in improving the reporting of sex and gender dimensions.

Despite the growing evidence illustrating important differences in health outcomes for women and men, sex and gender differences in COVID-19 interventional or observational studies are inadequately examined and reported. This highlights the necessity of renewing our commitment to the SAGER guidelines and working towards more gender sensitive research and reporting practices. This will ensure that research-based health interventions are equally safe and effective for women and men.