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Intimate partner violence (IPV) increases risk of traumatic brain injury (TBI). Physical assaults increase in frequency and intensity during pregnancy. The consequences of TBI during pregnancy (gravida TBI; gTBI) on offspring development is unknown, for which stress and inflammation during pregnancy worsen fetal developmental outcomes. We hypothesized that gTBI would lead to increased anxiety- and depression-related behavior, altered inflammatory responses and gut pathology, and distorted brain circuitry in mixed-sex offspring compared to mice born to control mothers. Pregnant dams received either diffuse TBI or sham injury (control) 12 days post-coitum. We found that male gTBI offspring were principal drivers of the gTBI effects on health, physiology, and behavior. For example, male, but not female, gTBI offspring weighed significantly less at weaning compared to male control offspring. At post-natal day (PND) 28, gTBI offspring had significantly weaker intralaminar connectivity onto layer 5 pre-frontal pyramidal neurons compared to control offspring. Neurological performance on anxiety-like behaviors was decreased, with only marginal differences in depressive-like behaviors, for gTBI offspring compared to control offspring. At PND42 and PND58, circulating neutrophil and monocyte populations were significantly smaller in gTBI male offspring than control male offspring. In response to a subsequent inflammatory challenge at PND75, gTBI offspring had significantly smaller circulating neutrophil populations than control offspring. Anxiety-like behaviors persisted during the immune challenge in gTBI offspring. However, spleen immune response and gut histology showed no significant differences between groups. The results compel further studies to determine the full extent of gTBI on fetal and maternal outcomes.

Traumatic brain injury (TBI) affects millions of individuals each year and is a leading cause of death and disability worldwide. TBI is heterogeneous and outcome is influenced by a combination of factors that include injury location, severity, genetics, and environmental factors. More recently, sex as a biological variable has been incorporated into TBI research, although there is conflicting literature regarding clinical outcomes in males versus females after TBI. We review the current clinical literature investigating sex differences after TBI. We focus our discussion on differences within contemporary gender categories to suggest that binary categories of male and female are not sufficient to guide clinical decisions for neurotrauma. Some studies have considered physiological variables that influence sex such as hormone cycles and stages in males and females pre- and post-TBI. These data suggest that there are phasic differences within male populations and within female populations that influence an individual's outcome after TBI. Finally, we discuss the impact of gender identity and expression on outcome after TBI and highlight the lack of neurotrauma research that includes non-binary individuals. Social constructs regarding gender impact an individual's vulnerability to violence and consequent TBI, including the successful reintegration to society after TBI. We call for incorporation of gender beyond the binary in TBI education, research, and clinical care. Precision medicine necessarily must progress beyond the binary to treat individuals after TBI.