An important factor mediating the incidence of traumatic brain injury (TBI) is a patient’s sex. Epidemiological reports have indicated that men are overrepresented among those patients with TBI who are less than 65 years of age while this pattern is reversed for those over the age of 65 years.1 As scientists gain a greater understanding of the similarities and differences between healthy human brains of men and women, TBI research is increasingly taking into account the potential influence a patient’s sex may play in determining their outcome.2

Laboratory studies of TBI have consistently found sex differences, with female animals often demonstrating a better outcome following experimental TBI.3 Conversely, human studies have been inconclusive, potentially because of the heterogeneous nature of TBI. Also important is injury severity and that the sexes may differ in the types of injuries sustained. This could arise from sex differences in mode of injury through to differences in premorbid brain morphology. Finally, the lack of age matching between the sexes may contribute to inconsistency of results, with greater mortality and worse functional outcome demonstrated in older people following TBI.4

To date, there has only been one systematic review of this topic. In 2000, Farace and Alves5 conducted a meta-analysis of gender differences on TBI outcome, finding that on average, outcome after TBI was worse in women than in men, with 17 of the 20 comparisons demonstrating a negative trend for women.

The current review adds to these earlier findings by systematically reviewing studies that examined sex differences in functional outcome measures following moderate to severe TBI in an attempt to determine whether women have better functional outcome.

METHOD

Studies which included measures of functional outcome that addressed at least three or more specific World Health Organization’s International Classification of Functioning, Disability and Health6 activity and participation domains—namely, general tasks and demands; communication; mobility; self care; domestic life; and major life areas—and used instruments with published psychometric criteria that were not solely self report, were considered in this review.

Studies were selected through searches of Medline, EMBASE, PsycINFO and CINAHL to 30 April 2007. Abstracts and titles were used to initially determine relevance to the review topic, and full text of potentially relevant articles were retrieved to assess the article for inclusion. The reference lists of retrieved articles were checked for any further relevant citations. Studies were included if they met specific methodological criteria (see table 2 in supplementary file available online). Methodological quality was assessed using a modified version of an established criteria list for prognostic studies.7

There was substantial heterogeneity in the eligible studies, and statistical pooling was not feasible. A strength of evidence synthesis was performed using the four levels of evidence for prognostic factors (strong, moderate, limited and inconclusive—see table 1 in the supplementary file online).8 Relative risks ratios, odds ratios (ORs) or significant associations (p<0.05) were used to determine the strength of evidence. When multivariate analysis was performed in the studies, these results were used to establish levels of evidence. Otherwise, results from univariate analysis were used. Further details of the analysis are presented in the supplementary file online.

RESULTS

Selection of studies and methodological quality

Figure 1 depicts the flow chart for identifying the included studies.

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Figure 1 Flow diagram of papers accepted and rejected during the selection process. TBI, traumatic brain injury.

Quality scores for each study are shown in table 1. More than half of the studies scored 5 points and thus were considered high quality. By far the greatest contribution to the methodological shortcomings of the remaining studies was failure to appropriately account for confounding variables (three out of the remaining five papers), and unequal numbers of complete follow-up between the sexes accounting for the other two studies not scoring 5 out of 5.

Study characteristics, outcome measures and results

The main characteristics of the included studies are shown in table 1. Of the 13 studies examined, only four had a primary aim to investigate sex differences in measures of functional outcome, with the remaining nine studies examining sex differences as a secondary analysis. Eight out of 13 were retrospective cohort studies. Roughly equal numbers of studies examined solely patients with severe TBI as those with a combination of moderate to severe TBI population (five vs six out of 13 studies) with the remaining two studies including mixed TBI severity. The time frame at which functional measures were assessed varied widely, ranging from a minimum of 3 months up to 24 years post injury, with the majority of papers reporting measures at 6 months (six out of 13 studies). A qualitative summary of the results is presented in the table 1.

Levels of evidence after stratification by study quality and overall direction of the evidence

Overall there was strong evidence that women do not achieve better functional outcomes following moderate to severe TBI. Two of the eight high quality studies reported that women had a worse outcome following TBI with the remaining six papers reporting no sex differences on their respective outcome measures. When considering the low quality studies, there was one positive finding indicating that women experience better outcome following TBI, and one negative finding reporting worse outcome in women. The remaining four low quality papers concluded there was no sex differences in the functional outcome measures examined.

DISCUSSION

This systematic review concludes that strong evidence is available suggesting that women do not have better functional outcome than men following moderate to severe TBI. This is contrary to the bulk of animal research indicating females experience better outcome compared with males.

However, the studies included in this systematic review do not consider a number of potentially relevant factors. Firstly, in the studies that reported a worse outcome in women (three out of 13), this pattern was observed in older females (likely to be post menopause), with no differences being noted between the sexes in the younger subgroups. Hormones such as progesterone and oestrogen may play a role in a patient’s response to brain injury.15 Briefly, it has been suggested that higher levels of progesterone relative to oestrogen reduce the complex cascade of events that accompanies TBI, known as secondary brain damage, by maintaining better immune function activity and protecting against physiological shock.16 The studies included do not report female hormonal status at the time of injury and issues such as the use of the contraceptive pill in the younger females and hormone replacement therapy in the older females are not considered. Secondly, it should be noted that most of the functional outcome measures used in studies included in this systematic review do not detail the men to women ratio in their original development and validation cohort. Therefore, limited outcome measurement sensitivity to sex differences could explain the negative result reported in this systematic review. Furthermore, one of the most common criticisms of scales such as the Glasgow Outcome Scale and Rancho Los Amigos Levels of Cognitive Functioning Scale is their lack of sensitivity to change in general and this is also a factor to consider.

Finally, the idea that time post injury may be an important factor in determining potential sex differences in functional outcome should be highlighted. In this review, Devitt et al17 reported that women between 7 and 24 years post injury experienced a better outcome, as measured by the Community Integration Questionnaire. The majority of the other studies had assessment periods that ranged from 3 to 18 months post injury. Thus it is possible that the reported female advantage following TBI is best demonstrated in longer term outcome where factors such as psychosocial influences start to come into effect.

In the previous systematic review, Farace and Alves5 reported that women had a worse outcome for 85% of the variables examined. Plausible reasons for the differing results are our different search period, inclusion criteria (particularly all TBI vs moderate to severe TBI) and which outcomes were evaluated. Without examining the methodological quality of the studies, Farace and Alves’ meta-analysis quoted an average effect size of −0.15 without associated confidence intervals. This simple average did not take into account the differing sample sizes between studies and therefore was not appropriately weighted. Furthermore, 10 out of the 20 individual effect sizes came from a single study,18 increasing the likelihood that they were correlated, a factor not addressed or adjusted for in the subsequent meta-analysis.

The current review presents strong evidence to suggest that, in contrast with the animal literature, women do not experience better functional outcomes than men following moderate to severe TBI. It is suggested that future studies should be designed with careful consideration of the complex issues surrounding human sex differences. Factors such as female hormonal status at the time of injury and other sources of heterogeneity such as age and injury severity should be addressed.