Underreporting of Sex-Specific Findings in Risk Factors for Unruptured Intracranial Aneurysms Open Access

Approximately 3% of individuals in the general population have an unruptured intracranial aneurysm (UIA) [1]. Rupture of a UIA causes aneurysmal subarachnoid hemorrhage (aSAH), a devastating subtype of stroke, with approximately one-third of patients dying and one-third remaining dependent on help of others [2].

Women are overrepresented in both the UIA and aSAH populations, with an overall two-thirds of patients being female [1, 3]. The reason women are more prone to develop UIA and aSAH is unknown. However, understanding this predisposition is of critical importance for improving preventative and treatment strategies.

While research on risk factors for the formation of UIAs is less extensive than for aSAH, a positive familial history of UIA, hypertension, cigarette smoking, and alcohol consumption have been associated with UIAs [3]. Sex differences in the strength of risk factor associations with UIA might contribute to the higher burden of UIA in women. Indeed, sex differences in risk factor associations have been reported for aSAH, where the association between smoking and aSAH is stronger in women than in men [4]. We confirmed this finding in a recent systematic review and meta-analysis of risk factors for aSAH, which we conducted concurrently with the present study on UIA [5]. It is unknown whether similar sex differences exist for UIAs. Therefore, we performed a systematic review of clinical risk factors for UIAs, with a specific aim to assess whether these risk factor associations are sex-dependent.

We systematically searched the electronic medical databases of PubMed, Embase, Emcare, Web of Science, and the Cochrane Library to identify all relevant literature from inception to March 2024. Since we conducted the systematic reviews of UIA and aSAH simultaneously, we combined search terms for both into one search string. Cohort or case-control studies were included if they reported on risk factors associated with the formation of saccular UIAs in an adult population. Selected risk factors included smoking, alcohol use, hypertension, hypercholesterolemia, physical activity, diabetes, and BMI and were preselected based on a previous 2005 meta-analysis [6]. UIA diagnosis had to be confirmed by neuroimaging, autopsy or International Classification of Diseases (ICD) codes. Two review authors independently assessed study eligibility and quality using an adapted version of the Newcastle-Ottawa Scale. Any disagreements were resolved by a third review author.

A total of 21 studies met the inclusion criteria. A summary of study characteristics is shown in Table 1. Eighteen of these studies included both women and men. Overall, a total of 347,907 participants and 8,698 UIA cases were included, of whom 178,417 (51%) participants were women and 5,773 (66%) of UIAs occurred in women. The overall quality of the included studies varied: two out of 21 were rated as low risk of bias across all domains, two had high or possible risk in one domain, and the remaining 17 had high or possible risk in two or more of the four domains. Among the 18 studies that included both sexes, 44% reported findings adjusted for sex in multivariable analyses. However, only one study (<6%) stratified its results by sex, making sex-stratified analyses not possible (shown in Fig. 1) [7]. This one study found similar associations of hypertension and diabetes with UIA in women and men.

The importance of considering sex in health and medical research has been increasingly recognized [28]. Yet, as our review shows, many studies still fail to report their results by sex, even when the data are available. Stratification by sex in less than 6% of studies on risk factors for UIA is exceptionally low compared to other fields of cardiovascular medicine, where sex-stratified data are reported in up to 36% of studies [29, 30]. This underreporting may reflect a persisting lack of awareness or prioritization of incorporating sex as a relevant variable in reporting research results. Another contributing factor may be that many scientific journals still do not require sex-specific analyses in their publication guidelines, which could reinforce this underrecognition. Additionally, a commonly expressed concern is that sex-stratified analyses might be underpowered to yield meaningful results. While a single study might indeed not be sufficient to reach definitive conclusions, the publication of sex-stratified results would still facilitate future meta-analyses, such as the one we intended to perform here. Collectively, such studies could help increase our understanding of sex differences in UIA and unveil reasons for the female predominance. To address these challenges, funders and editorial policies should actively encourage the incorporation of sex-specific results. Additionally, special issues and themed editions, such as the Go Red for Women edition in Stroke, can provide positive reinforcement and raise awareness of this topic. In summary, we highlight the need for the reporting of sex-stratified results in the field of UIA research.

The authors wish to thank Jan W. Schoones from the Directorate of Research Policy at Leiden University Medical Center for developing the search strategy.

A statement of ethics is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

Y.M.R. received funding from the Dutch Heart Foundation (Dekker Grant 03-001-2022-0157) and the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (grant agreement 852173). S.A.E.P. is supported by a VIDI Fellowship from the Dutch Organisation for Health Research and Development (ZonMw) (09150172010050).

M.J.A.E,. M.A., and S.R. performed the systematic review. M.J.A.E. wrote the manuscript. S.A.E.P., H.M.R., and Y.M.R. critically revised the manuscript. All authors contributed to the article and approved the submitted version.

The data that support the findings of this study are not publicly available due to an ongoing systematic review but are available from the corresponding author upon reasonable request.