Systematic Review of Sex and Gender Effects in Traumatic Brain Injury: Equity in Clinical and Functional Outcomes

Abstract

Background: Although traumatic brain injury (TBI) is a leading cause of death and disability in male and female patients worldwide, little is known about the effect of sex and gender on TBI outcomes. Objectives: This systematic review summarizes the evidence on the effect of sex and gender on core TBI outcomes. Methods: All English-language studies from six literature databases that addressed core outcomes in adults with TBI and included sex or gender, TBI severity, and age in their analyses were considered eligible. Two reviewers extracted data, and two reviewers assessed study quality using tools recommended by the National Institutes of Health. The results were sorted according to time post-injury, injury severity, gender equity ranking of the study's country of origin, and outcomes studied. The results from the included studies were grouped based on the approach taken in reporting their respective findings. Results and Limitations: Of 172 articles assessed, 58 studies were selected, comprising 1, 265, 955 participants with TBI (67% male across all studies) of all injury severities. All studies were conducted in countries with a very high or high human development index, while the Gender Inequality Index (GII) varied. While the heterogeneity across studies limited any meaningful conclusions with respect to the role of sex and gender, we did observe that as gender equality ranking improved, differences between male and female participants in outcomes would diminish. Inclusion of social equity parameters in the studies was limited. Conclusions and Implications: The non-uniform findings observed bring forth the need to develop and use a comprehensive and consistent methodology in the study of sex and gender post-TBI, incorporating social equity parameters to uncover the potential social underpinnings of gender effects on health and functional outcomes. Systematic Review Registration: CRD42018098697.

Keywords: best-evidence synthesis; gender equality; outcomes; sex differences; social equity; traumatic brain injury.

Figure 1

PRISMA flow diagram. Flowchart depicting study selection process and outcome. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2

Findings overview overall, by outcome. The results are stratified according to assessed outcome. The height of the bar is only an indicator of assessment frequency at a certain point in time.

Figure 3

Overview of Findings by injury severity and post-injury phase. The results are stratified according to injury severity, and whether the baseline outcome assessment was conducted prior to, at, or following the 3-month post-injury period. The height of the bar is only an indicator of assessment frequency at a certain point in time.

Figure 4

Statistically significant sex/gender-related results reported as OR/RR/HR (CI). *The RBCT treatment and dementia outcome studies reported risk ratios (A), the stroke outcome studies reported hazard ratios (B), and the rest reported odds ratios. (A) The outcome odds for female relative to male persons. (B) The outcome odds for male relative to female persons. The error bars represent a 95% confidence interval. The superscript letters indicate the GII rank of the country where the study was conducted (lower rank indicates lower gender inequality), the post-injury phase (A, acute; C, chronic; and NR, not reported), and injury severity (M, mild; M-S, moderate-to-severe; S, severe; and ALL, all severities). GII, Gender Inequality Index; RBCT, red blood cell transfusion.

Figure 5

Non-statistically significant sex/gender-related results reported as OR/RR/HR (CI). (A) The outcome odds for female relative to male persons. (B) The outcome odds for male relative to female persons. The error bars represent a 95% confidence interval. The superscript letters indicate the post-injury phase (A, acute; C, chronic; and NR, not reported) and injury severity (M, mild; M-S, moderate-to-severe; S, severe; ALL, all severities; and HBI, hemorrhagic brain injury). *No reference groups in the sex/gender analysis (86).

Figure 6

Effect sizes of explained factors/variance investigated in relation to post-TBI outcomes in multivariate regression analyses. This figure represents select findings for comparative purposes (all outcomes available in Supplementary Figure 5). All analyses included sex/gender. For the * outcomes, the proportions correspond to the partial R². For all other outcomes, the proportions correspond to the β coefficients. Total corresponds to the total variance explained by the model (R²). Only statistically significant factors are included as explaining variance, given that the cutoff p-values were not consistently reported. The superscript letters indicate post-injury phase (A, acute; C, chronic; and NR, not reported) and injury severity (M, mild; M-S, moderate-to-severe; S, severe; and ALL, all severities). The bolded factors in the “Controlled for” boxes indicate those that have been linked to sex and/or gender.

Figure 7

Logic model of sex and gender effects on outcomes of TBI. The implications are that biological and behavioral vulnerability to injury and gender disparities in norms and role expectations make certain groups of male and female persons be prone to a more favorable or adverse outcome due to their unique interactions between biological, behavioral, sociocultural elements preceding, at the time of, and following the injury. TBI, traumatic brain injury. This figure was modified from a previously published framework (22).